JP2018502894A - Methods for treating or preventing atherothrombotic events in patients with a history of myocardial infarction - Google Patents

Abstract

The disclosure includes administering to a patient a pharmaceutical composition comprising 60 mg of ticagrelor twice a day, in a recognized patient, cardiovascular death, myocardial infarction, or stroke It is related with the method of reducing the rate.

Description

  This application is filed under US Patent Act 119, US Provisional Patent Application No. 62 / 108,453, filed January 27, 2015; US Provisional, filed February 5, 2015. Patent application 62 / 112,318; US provisional patent application 62 / 117,871 filed February 18, 2015; US provisional patent application filed March 13, 2015 No. 62 / 133,224; U.S. Provisional Patent Application No. 62 / 133,327, filed Mar. 14, 2015; U.S. Provisional Patent Application No. 62, filed May 1, 2015. No. 156,083; U.S. Provisional Patent Application No. 62 / 156,823 filed on May 4, 2015; and U.S. Provisional Patent Application No. 62 / filed on August 28, 2015. Priority of specification 211,635 Claims of profits.

  The present disclosure relates generally to methods of treating or preventing antithrombotic events in patients with a history of acute coronary syndrome (ACS) or myocardial infarction (MI). In one aspect, the disclosure provides in a patient comprising administering to a patient with a history of myocardial infarction twice a day a pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier. Relates to a method for reducing the rate of cardiovascular death, myocardial infarction, or stroke. In another aspect, the disclosure comprises administering to a patient with a history of acute coronary syndrome twice a day a pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier. The invention relates to a method of reducing the rate of cardiovascular death, myocardial infarction, or stroke in a patient.

Ticagrelor is a direct acting reversible binding P2Y ₁₂ receptor antagonist that inhibits platelet activation and aggregation mediated by the P2Y ₁₂ ADP receptor. Ticagrelor, a cyclopentyl lysolopyrimidine, does not belong to the same chemical class as other available antiplatelet agents. Currently, prominent antiplatelet agents include the cyclooxygenase inhibitor acetylsalicylic acid (also known as ASA or aspirin) and the thienopyridines clopidogrel, ticlopidine, and prasugrel. In addition to acting as a P2Y ₁₂ receptor antagonist, ticagrelor is also known to increase local endogenous adenosine levels by inhibiting diffuse nucleoside transporter-1 (ENT-1). Adenosine is formed locally at sites of hypoxia and tissue injury through the degradation of released adenosine triphosphate and diphosphate (ATP and ADP). Since adenosine degradation is essentially limited to the intracellular space, inhibition of ENT-1 by ticagrelor increases the local extracellular concentration and thereby enhances the local adenosine response. provide. Adenosine has been demonstrated to have several effects, including vasodilation, cardioprotection, platelet inhibition, inflammation regulation, and dyspnea induction, which may contribute to the clinical profile of ticagrelor .

Ticagrelor also has its chemical name, (1S, 2S, 3R, 5S) -3- [7-{[(1R, 2S) -2- (3,4-difluorophenyl) cyclopropyl] amino} -5- ( Propylthio) -3H- [1,2,3] -triazolo [4,5-d] pyrimidin-3-yl] -5- (2-hydroxyethoxy) cyclopentane-1,2-diol is also known. Empirical formula Chikagureroru _{is C 23 H 28 F 2 N 6} O 4 S, its molecular weight is 522.57Da. The chemical structure of ticagrelor is as follows.

  At room temperature, ticagrelor is a crystalline powder with a water solubility of approximately 10 μg / mL.

Ticagrelor can be taken with or without food. In patients, absorption of ticagrelor occurs at the intermediate time to reach peak plasma concentration (c _max ) of ticagrelor (t _max ) 1.5 hours after administration, with a t _max range of 1.0 to 4.0 hours. . The formation of AR-C124910XX, the major circulating metabolite from ticagrelor, occurs at a median _{tmax of} 2.5 hours and in the range of 1.5-5.0 hours. The average absolute bioavailability of ticagrelor is about 36% (range 30% -42%). Ingestion of a high fat diet does not affect the peak plasma concentration (c _max ) of ticagrelor but results in a 21% increase in the concentration time curve integral (AUC).

Furthermore, ticagrelor as a milled tablet mixed with water, administered orally or intragastrically via a nasogastric tube, is bioequivalent to all tablets (ticagrelor and its main metabolite AR For C124910XX, AUC and c _max within 80% to 125%, medium t _max is 1.0 hour for ticagrelor (range 1.0-4.0 hours), 2.0 hour for AR-C124910XX (range) 1.0 to 8.0 hours). The steady state distribution capacity of ticagrelor is 88L. Ticagrelor and AR-C124910XX bind extensively to human plasma proteins (> 99%).

Ticagrelor offers several advantages over other commercially available P2Y ₁₂ receptor antagonists. For example, ticagrelor is not a prodrug and therefore does not require metabolic activation. Furthermore, administration of ticagrelor results in a rapid onset of antiplatelet effects (within 2 hours in most patients), low inter-individual variability, and reversibility when compared to thienopyridines such as clopidogrel, ticlopidine, and prasugrel. Resulting in a quicker offset of platelet inhibition.

  A randomized, double-blind, Platelet Inhibition and Patient Outcomes (PLATO) clinical trial was conducted in patients representing the entire spectrum of acute coronary syndrome compared to 75 mg of clopidogrel combined with once-daily aspirin. 90 mg ticagrelor in combination with two aspirins was tested. The results of the PLATO study showed that ticagrelor reduced ischemic events for up to 1 year after acute coronary syndrome. In 2011, BRILINTA® containing ticagrelor was approved by the US Food and Drug Administration (USFDA) in view of PLATO clinical trial results.

  Myocardial infarction is a global problem. In the United States alone, the incidence of acute myocardial infarction is approximately 600,000 cases per year, and nearly 8 million people have a history of myocardial infarction. Furthermore, patients who have had myocardial infarction are at increased risk for recurrent ischemic events. A recent APOLLO RWE clinical trial showed that approximately 1 in 5 patients who remained asymptomatic for 12 months after myocardial infarction had recurrent myocardial infarction, stroke, or vascular accident in the following 36 months I found that I would die. Thus, patients with a history of myocardial infarction may receive special benefits from thorough secondary prevention.

An important element in the pathobiology of cardiovascular ischemic events is activated platelets. Correspondingly, antiplatelet therapy is the basis for the prevention of such events. To that end, aspirin reduces ischemic risk in patients with acute coronary syndrome as well as in long-term secondary prevention. Addition of P2Y ₁₂ receptor antagonist to aspirin (referred to as double antiplatelet therapy or DAPT) further reduces the risk of ischemic events in this population during the first year after acute coronary syndrome Has been shown previously.

However, the role of P2Y ₁₂ receptor antagonists in long-term secondary prevention after myocardial infarction has not been established. Both US and European practice guidelines currently recommend treatment with P2Y ₁₂ receptor antagonists for up to one year after myocardial infarction. One preferred P2Y ₁₂ receptor antagonist in patients with acute coronary syndrome is ticagrelor, a direct agent that reversibly binds, which achieves high levels of platelet inhibition and low inter-individual variability. Have In patients with acute coronary syndrome, when added to aspirin for up to 1 year, ticagrelor 90 mg twice a day is a significant adverse effect, including cardiovascular mortality, compared to 75 mg clopidogrel once a day. Decreased cardiovascular events and steadily increased benefits over time.

  Following the PLATO, the heart of the heart of the prevention of cardiovascular events in the patient's heart with the heart attack of the heart attack that used the prevention of the heart attack attacking ticaglor and the heart of the heart (PEGASUS-TIMI 54) study (also referred to herein as the PEGASUS study or PEGASUS study) was designed to provide long-term treatment with ticagrelor added to low-dose aspirin in stable patients with a history of myocardial infarction Therapy will reduce the risk of serious adverse cardiovascular events Hypothesis that has been verified. Aspirin is known to reduce the risk of ischemic events in patients with acute coronary syndrome and in secondary prevention of myocardial infarction. The majority of patients in the PEGASUS study receive a daily maintenance dose of 75 mg to 150 mg of aspirin, and less than 0.1% of patients have a daily maintenance dose of aspirin greater or less than 75 mg to 150 mg. Was administered.

  Bleeding represents a significant safety issue for all antiplatelet drugs. Antiplatelet agents, inherent to their pharmacodynamic effects, increase the risk of bleeding. There is a risk of bleeding of all severities, from minimally troublesome bleeding to life-threatening lethal bleeding, which may occur during long-term out-of-hospital treatment or as a result of heart and other surgery .

  Furthermore, it was previously established that ticagrelor is metabolized by the liver and liver dysfunction increases the risk of bleeding and other adverse events. Recognizing the balance between ischemic and bleeding risks and antithrombotic therapy and considering that there may be differences in the strength of antiplatelet therapy required between acute and chronic situations, the PEGASUS trial is Twice daily dose at 90 mg tested with PLATO, as well as lower twice a day at 60 mg to see if lower intensity in the chronic phase of long-term therapy improves efficacy and bleeding balance Two strengths of dose ticagrelor therapy were evaluated.

  Prior to the PEGASUS study, the optimal strength of platelet inhibition for long-term treatment was unknown. Twice daily at less than 60 mg of ticagrelor was also considered for studies in the PEGASUS study, but modeling has been shown, for example, that platelet aggregation (IPA) of ticagrelor 45 mg twice daily is greater than clopidogrel 75 mg twice daily. ) Predicted no sustained level of inhibition. In addition, the modeling shows that the intra-individual variation of IPA increases with decreasing dose of ticagrelor, and the intra-individual variation of IPA is twice daily with 45 mg ticagrelor compared to 90 mg twice daily with ticagrelor. Expected to be 2-3 times larger. While modeling suggested that ticagrelor 60 mg twice a day could produce sustained IPA levels that were higher than clopidogrel 75 mg twice a day with acceptable intra-individual variability, The twice daily dosing regimen of ticagrelor 60 mg has not been tested in humans prior to the PEGASUS study. The USFDA label revised December 13, 2013 for BRILINTA® drugs refers only to PLATO studies.

  After PLATO, long-term therapy with ticagrelor added to aspirin is associated with increased risk of adverse cardiovascular events in stable patients with a history of myocardial infarction in the experimental group compared to placebo administered in the placebo-controlled group. In order to evaluate whether to decrease, the PEGASUS-TIMI 54 clinical trial (Prevention of Cardiovascular Events in Patients with Prior Heart Attaching Ticator Colored to Pacebo Prevention of cardiovascular events in patients with a history of seizures)) was designed.

  In a first aspect, disclosed herein is a randomized, double-blind clinical trial that requires reducing the risk of cardiovascular mortality, myocardial infarction, or stroke in a patient in an experimental treatment group A method comprising the step of administering to an approved patient an amount of ticagrelor and aspirin in an amount that effectively reduces the risk of cardiovascular death, myocardial infarction, or stroke in the patient, the experimental treatment group Patients who are effectively reduced in risk compared to placebo and who need to reduce the risk of cardiovascular mortality, myocardial infarction, or stroke, are treated with placebo and aspirin The placebo-compared treatment group was a clopidogrel combination with aspirin, which was an activity comparison treatment group in the PLATO study. Patients in both the experimental and placebo comparison groups had a history of myocardial infarction within 12-36 months preceding treatment in the experimental treatment group and placebo comparison group .

  This method was tested and found to be effective in the PEGASUS study, a randomized, double-blind clinical trial involving more than 21,000 patients. Following a comprehensive review of the PEGASUS study results, the USFDA has approved a label extension for BRILINTA® drugs that includes administering 60 mg of ticagrelol to patients with a history of myocardial infarction. The expanded indication of BRILINTA was approved under the USFDA Priority Review, a designation given to pharmaceuticals that the USFDA has determined may provide significant improvements in the treatment, prevention, or diagnosis of the disease . The USFDA label of the September 2015 revision of the BRILINTA® drug refers to both PLATO and PEGASUS studies.

  In some embodiments of the first aspect, the method also includes the risk of lethal bleeding in patients receiving ticagrel in the experimental treatment group compared to patients receiving placebo in the placebo comparison treatment group. Shows a downward trend.

  In some embodiments of the first aspect, ticagrelor is administered twice daily at 90 mg in the experimental treatment group. In some embodiments of the first aspect, ticagrelor is administered twice daily at 60 mg in the experimental treatment group.

  In some embodiments of the first aspect, a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier is administered twice daily. In some embodiments of the first aspect, in the experimental treatment group, a pharmaceutical composition comprising 60 mg of ticagrelor and a pharmaceutically acceptable carrier is administered twice daily. In some embodiments of the first aspect, in the experimental treatment group, a pharmaceutical composition comprising ticagrelor and a pharmaceutically acceptable carrier is administered in a tablet form formulation that is administered orally.

In a second aspect, disclosed herein comprises administering to a patient twice a day a pharmaceutical composition comprising 60 mg of ticagrelor and a pharmaceutically acceptable carrier, wherein A method to reduce the composite endpoint rate of cardiovascular death, myocardial infarction, or stroke in a recognized need,
The patient has a history of myocardial infarction;
The patient is also administered a daily maintenance dose of 75 mg to 150 mg of aspirin;
Compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to the patient, the composite endpoint rate in the patient is reduced.

  The effectiveness of the disclosed methods of the first and second aspects for reducing cardiovascular mortality, myocardial infarction, or stroke rate was demonstrated by the PEGASUS-TIMI 54 study.

  In some embodiments of the first and second aspects, the daily maintenance dose of aspirin is between 75 mg and 100 mg.

  In some embodiments of the first and second aspects, the patient has at least 12 months prior to twice daily administration of a pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier. And has a history of myocardial infarction.

  In some embodiments of the first and second aspects, the patient has 12 to 36 months preceding twice daily administration of a pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier. In between, has a history of myocardial infarction.

  In some embodiments of the first and second aspects, the patient has a history of myocardial infarction as a result of acute coronary syndrome. In some further embodiments of the first and second aspects, a medicament comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier for a portion of 12 months after acute coronary syndrome prior to administration The composition was administered to patients twice a day. In some further embodiments of the first and second aspects, a pharmaceutical composition comprising 90 mg ticagrelor and a pharmaceutically acceptable carrier for 12 months after acute coronary syndrome prior to administration, The patient was dosed twice daily. In still some further embodiments of the first and second aspects, prior to administration, 180 mg prior to twice daily administration of a pharmaceutical composition comprising 90 mg ticagrelor and a pharmaceutically acceptable carrier. A pharmaceutical composition comprising an initial loading dose of ticagrelor was administered to a patient.

  In some embodiments of the first and second aspects, an initial loading dose of ticagrelor is not required. In some further embodiments of the first and second aspects where an initial loading of ticagrelor is not required, the patient is twice a day of a pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier. Have a history of myocardial infarction for at least 12 months prior to administration of

In some embodiments of the first and second aspects, the method satisfies at least one of the following conditions:
(A) The method quantifies the absolute risk of a composite endpoint of cardiovascular mortality, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Reduced to
(B) The method is less than 1 relative to the combined endpoint of cardiovascular death, myocardial infarction, or stroke, compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Brings risks;
(C) The method reduces the Kaplan-Meier rate for combined endpoints of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Reduce numerically;
(D) The method is statistically associated with a composite endpoint rate of cardiovascular death, myocardial infarction, or stroke compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Cause a significant reduction in
(E) the method is statistically associated with a combined endpoint of cardiovascular death, myocardial infarction, or stroke, as compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Results in a relative risk of significantly less than 1;
(F) The method results in a Kaplan-Meier rate of approximately 7.8% for the composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years;
(G) The method results in a Kaplan-Meier rate of 7.8% at the composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years;
(H) the method is in time to the first composite endpoint of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient; Resulting in a hazard ratio of less than 1;
(I) Percentage of patients with a combined endpoint event of cardiovascular death, myocardial infarction, or stroke as compared to a regimen where the method is administered daily maintenance doses of 75 mg to 150 mg of aspirin alone to the patient Results in a numerical decline;
(J) when the method is in time to the first composite endpoint of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient; Resulting in a statistically significant hazard ratio of less than 1;
(K) The first composite endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg aspirin alone Results in a hazard ratio of approximately 0.84;
(L) The first combined endpoint of cardiovascular mortality, myocardial infarction, or stroke at 3 years compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg of aspirin alone Results in a hazard ratio of 0.84
(M) The first composite endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg of aspirin alone Results in a hazard ratio of 0.74 to 0.95;
(N) The first combined endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg of aspirin alone A hazard ratio of 0.74 to 0.95 of time to 95% confidence interval;
(O) the absolute absolute composite endpoint of cardiovascular mortality, myocardial infarction, or stroke at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Reduce risk by approximately 1.27%;
(P) the absolute absolute of the combined endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Reduce risk by 1.27%;
(Q) The method is a compound endpoint of cardiovascular death, myocardial infarction, or stroke of 1 to 360 days compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Results in a relative risk reduction of approximately 17%;
(R) The method has a combined endpoint of cardiovascular death, myocardial infarction, or stroke of 1 to 360 days compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a 17% relative risk reduction;
(S) Kaplan, a composite endpoint of 3-year cardiovascular mortality, myocardial infarction, or stroke, as compared to a dosing regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg aspirin alone Reduce the Meyer rate by approximately 1.2%;
(T) Kaplan, a composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg aspirin alone -Decrease Meyer rate by 1.2%;
(U) The method has a combined endpoint event of cardiovascular mortality, myocardial infarction, or stroke at year 3 compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. The percentage of a patient is reduced by approximately 1.3%; or (v) the cardiovascular system at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Reduces the percentage of patients with compound endpoint events of systemic death, myocardial infarction, or stroke by 1.3%.

In some embodiments of the first and second aspects, the method satisfies at least one of the following conditions:
(A) The method does not result in a hazard ratio of more than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
(B) The method resulted in a hazard ratio nominally greater than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Absent;
(C) the method does not pose a relative risk of more than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
(D) The method resulted in a nominally significantly greater than 1 relative risk for lethal hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Absent;
(E) The method does not pose a relative risk of more than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
(F) The method does not pose a nominally significantly greater than 1 relative risk for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. ;
(G) A numerical increase of less than 0.5 in the number of TIMI major bleeding events per 100 patient years compared to a dosing regimen where the daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Bring about;
(H) The method provides a numerical increase of 0.44 in the number of TIMI major bleeding events per 100 patient years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about;
(I) The method does not result in a numerical increase in the number of lethal bleeding events per 100 patient years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
(J) The method increases the number of intracranial hemorrhage events per 100 patient years by a numerical increase of 0.05 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about;
(K) The method reduces the Kaplan-Meier rate of lethal bleeding at 3 years to less than 0.05% compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Or (l) the method is 0.20% in Kaplan-Meier rate of intracranial hemorrhage for 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Results in less than a difference.

  In some embodiments of the first and second aspects, no overall difference in method safety or effectiveness is observed between elderly and young patients.

  In some other embodiments of the first and second aspects, the relative risk reduction of cardiovascular death, myocardial infarction, or stroke due to ticagrelor is similar regardless of renal function. In some embodiments of the first and second aspects, a pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier is administered to a patient twice a day for up to 47 months.

  In some embodiments of the first and second aspects, the method comprises a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier, and a daily maintenance dose of 75-100 mg of aspirin. Effective in reducing the rate of cardiovascular mortality, myocardial infarction, or stroke in patients, as much as methods administered twice daily to patients.

  In some embodiments of the first and second aspects, the method comprises a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier, and a daily maintenance dose of 75-100 mg of aspirin. Reduces the rate of irreversible harm to the patient as compared to methods administered to the patient twice daily.

  In some embodiments of the first and second aspects, the method comprises a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier, and a daily maintenance dose of 75-100 mg of aspirin. Reduces the combined endpoint rate of cardiovascular mortality, myocardial infarction, stroke, intracranial hemorrhage, or lethal hemorrhage compared to methods administered to patients twice daily.

  In some embodiments of the first and second aspects, the method improves the risk-benefit profile of ticagrelor administered in an aspirin background. In some further embodiments, the method comprises administering a pharmaceutical composition comprising 90 mg ticagrelor and a pharmaceutically acceptable carrier, and a daily maintenance dose of 75-100 mg aspirin to a patient twice a day. Improve the risk-benefit profile compared to the method used.

  In some embodiments of the first and second aspects, the method comprises a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier, and a daily maintenance dose of 75-100 mg of aspirin. , Resulting in a net clinical benefit compared to methods administered twice daily to patients.

  In some embodiments of the first and second aspects, the method comprises a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier, and a daily maintenance dose of 75-100 mg of aspirin. Compared to methods administered to patients twice a day, the composite endpoint rate of cardiovascular death, myocardial infarction, stroke, fatal TIMI major bleeding is reduced.

In a third aspect, disclosed herein comprises administering to a patient twice a day a pharmaceutical composition comprising 60 mg of ticagrelor and a pharmaceutically acceptable carrier, wherein A method to reduce the combined endpoint rate of cardiovascular death, myocardial infarction, or stroke in a recognized need,
The patient has or had had acute coronary syndrome;
The patient is also administered a daily maintenance dose of 75 mg to 150 mg of aspirin;
Compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to the patient, the composite endpoint rate in the patient is reduced.

  In some embodiments of the third aspect, the patient has acute coronary syndrome.

  In some embodiments of the third aspect, the patient had acute coronary syndrome.

  In some embodiments of the third aspect, the patient has a history of myocardial infarction.

  In some embodiments of the third aspect, the patient has a history of myocardial infarction as a result of acute coronary syndrome.

  In some embodiments of the third aspect, the daily maintenance dose of aspirin is 75 mg to 100 mg.

In a fourth aspect, disclosed herein comprises administering to a patient twice a day a pharmaceutical composition comprising 60 mg of ticagrelor and a pharmaceutically acceptable carrier, wherein A method to reduce the composite endpoint rate of cardiovascular death, myocardial infarction, or stroke in a recognized need,
The patient has a history of myocardial infarction, or the patient has or had acute coronary syndrome,
The patient is also administered a daily maintenance dose of 75 mg to 150 mg of aspirin;
Compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to the patient, the composite endpoint rate in the patient is reduced.

  In some embodiments of the fourth aspect, the daily maintenance dose of aspirin is 75 mg to 100 mg.

  In some embodiments of all aspects, a pharmaceutical composition comprising 60 mg of ticagrelor and a pharmaceutically acceptable carrier can be taken with or without food.

  In some embodiments of all aspects, a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier can be taken with or without food.

  In some embodiments of all aspects, the methods disclosed herein are interrupted 5 days prior to surgery at significant risk of bleeding and reunited as soon as possible after hemostasis is achieved. .

  In some embodiments of all aspects, the pharmaceutical composition is a solid oral dosage form. In some embodiments of all aspects, the pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier is a bulking agent present in an amount of 20% to 70% by weight, 3% to 6%. Formulated as a solid oral dosage form further comprising a binder present in an amount of 2%, a disintegrant present in an amount of 2% to 6% by weight, and a lubricant present in an amount of 0.5% to 1% by weight. The In still some further embodiments of all aspects, the pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier comprises mannitol and dicalcium phosphate present in an amount of 20% to 70% by weight. Of hydroxypropyl cellulose present in an amount of 3% to 6% by weight, sodium starch glycolate present in an amount of 3% to 6% by weight, and stearic acid present in an amount of 0.5% to 1% by weight Formulated as a solid oral dosage form further comprising magnesium.

  In some further embodiments of all aspects, a pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier is formulated as a tablet and administered orally.

  In some embodiments of all aspects, the pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier is a bulking agent present in an amount of 20% to 70% by weight, 3% to 6%. Formulated as an orally administered tablet, further comprising a binder present in an amount of 2%, a disintegrant present in an amount of 2% to 6% by weight, and a lubricant present in an amount of 0.5% to 1% by weight. Is done. In still some further embodiments of all aspects, the pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier comprises mannitol and dicalcium phosphate present in an amount of 20% to 70% by weight. Of hydroxypropyl cellulose present in an amount of 3% to 6% by weight, sodium starch glycolate present in an amount of 3% to 6% by weight, and stearic acid present in an amount of 0.5% to 1% by weight Formulated as an orally administered tablet, further comprising magnesium.

  In some other embodiments of all aspects, the pharmaceutical composition comprising 60 mg of ticagrelor and a pharmaceutically acceptable carrier comprises mannitol, dicalcium phosphate, sodium starch glycolate, hydroxypropylcellulose, stearic acid Formulated as an orally administered tablet further comprising magnesium, hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol 400, ferric black oxide, and ferric red oxide. In still some other embodiments of all aspects, the pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier comprises mannitol, dicalcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, Formulated as an orally administered tablet further comprising magnesium stearate, hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol 400, black ferric oxide, and ferric red oxide.

  In some embodiments of all aspects, a pharmaceutical composition comprising 60 mg of ticagrelor and a pharmaceutically acceptable carrier is formulated as an orally administered tablet as described in Table 1.

  In some embodiments of all aspects, the pharmaceutical composition comprising 90 mg ticagrelor and a pharmaceutically acceptable carrier is a bulking agent present in an amount of 20% to 70% by weight, 3% to 6%. Formulated as a solid oral dosage form further comprising a binder present in an amount of 2%, a disintegrant present in an amount of 2% to 6% by weight, and a lubricant present in an amount of 0.5% to 1% by weight. The

  In still some further embodiments of all aspects, the pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier comprises mannitol and dicalcium phosphate present in an amount of 20% to 70% by weight. Of hydroxypropyl cellulose present in an amount of 3% to 6% by weight, sodium starch glycolate present in an amount of 3% to 6% by weight, and stearic acid present in an amount of 0.5% to 1% by weight Formulated as a solid oral dosage form further comprising magnesium.

  In some further embodiments of all aspects, a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier is formulated as a tablet and administered orally.

  In some embodiments of all aspects, the pharmaceutical composition comprising 90 mg ticagrelor and a pharmaceutically acceptable carrier is a bulking agent present in an amount of 20% to 70% by weight, 3% to 6%. Formulated as an orally administered tablet, further comprising a binder present in an amount of 2%, a disintegrant present in an amount of 2% to 6% by weight, and a lubricant present in an amount of 0.5% to 1% by weight. Is done. In still some further embodiments of all aspects, the pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier comprises mannitol and dicalcium phosphate present in an amount of 20% to 70% by weight. Of hydroxypropyl cellulose present in an amount of 3% to 6% by weight, sodium starch glycolate present in an amount of 3% to 6% by weight, and stearic acid present in an amount of 0.5% to 1% by weight Formulated as an orally administered tablet, further comprising magnesium.

  In some other embodiments of all aspects, the pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier comprises mannitol, dicalcium phosphate, sodium starch glycolate, hydroxypropylcellulose, stearic acid Formulated as an orally administered tablet further comprising magnesium, hydroxypropylmethylcellulose, titanium dioxide, talc, polyethylene glycol 400, and yellow ferric oxide.

  In some further embodiments of all aspects, the orally administered tablet comprising 90 mg of ticagrelor is a round biconvex yellow film-coated tablet labeled with “90” on one side “T”. is there.

  In some further embodiments of all aspects, the orally administered tablet comprising 60 mg ticagrelor is a round biconvex pink film-coated tablet labeled with “60” on one side “T”. is there.

  In some embodiments of all aspects, a tablet comprising ticagrelor may be crushed, mixed with water, and taken. In some other embodiments of all aspects, the pharmaceutical composition comprising ticagrelor and a pharmaceutically acceptable carrier may be administered through the nasogastric tube (CH8 or higher).

  In some embodiments of all aspects, a patient who missed administration of a pharmaceutical composition comprising ticagrelor and a pharmaceutically acceptable carrier then comprises ticagrelor and a pharmaceutically acceptable carrier. The resulting pharmaceutical composition (the patient's next pharmaceutical composition) is administered at the scheduled time.

  The dosage unit forms of the present disclosure can be manufactured by compressing or squeezing an admixture or composition such as a powder or granules under pressure to form a stable three-dimensional shape (eg, a tablet). As used herein, “tablet” includes compressed dosage unit forms of all shapes and dimensions, whether coated or uncoated.

  The expression “dosage unit form” as used herein refers to a physically discrete unit of drug suitable for the patient to be treated. In general, a compressed mixture has a greater density than the mixture before it is compressed. The dosage unit forms of the present disclosure can have almost any shape, including concave and / or convex, round or square, and round to straight shapes. In some embodiments, the compressed dosage form of the present disclosure comprises a round tablet having a flat surface. The solid pharmaceutical dosage forms of the present disclosure can be prepared by any compression and squeezing method known to those skilled in the art of forming compressed solid pharmaceutical dosage forms. In certain embodiments, the pharmaceutical compositions provided herein may be formulated using conventional methods known to those skilled in pharmaceutical formulation, for example, as described in related textbooks. For example, Remington: The Science and Practice of Pharmacy, 21st Ed. Lippincott Williams & Wilkins, Baltimore, Md. (2003); Ansel et al. , Pharmaceutical Dosage Forms And Drug Delivery Systems, 7th Edition, Lipcottot Williams & Wilkins, (1999); The Handbook of Pharmaceutical 4 Eds. , American Pharmaceuticals Association (2003); Gibson, Pharmaceutical Preformation And Formulation, CRC Press (2001), these references are known to those skilled in the art of pharmaceutical formulations. Incorporated herein by reference.

  As mentioned above, the composition pharmaceutical of the present disclosure comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, is suitable for the particular dosage form desired. Any and all suitable solvents, diluents or other liquid vehicles, dispersions or suspension aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc. including. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.M. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used to formulate pharmaceutically acceptable compositions and known techniques for preparing them. Any conventional carrier medium may interact with ticagrelor, such as by causing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition. Except where it is non-conforming, its use is contemplated within the scope of this disclosure. Some examples of materials that can serve as a suitable pharmaceutically acceptable carrier include: ion exchangers; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphate Glycine; sorbic acid or potassium sorbate; partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; Polyvinyl pyrrolidone; Polyacrylate; Wax; Polyethylene-polyoxypropylene-block polymer; Wool fat; Sugars such as lactose, glucose, and sucrose; Starches such as corn starch and potato starch; Carboxymethyl cellulose Cellulose and its derivatives such as sodium, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and Oils such as soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; Including, but not limited to, isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solution; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate. According to the judgment of the formulator of the art beauty, colorants, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

  In some embodiments, the pharmaceutical composition comprising ticagrelor and a pharmaceutically acceptable carrier further comprises a bulking agent, a binder, a disintegrant, and a lubricant. In some embodiments, the bulking agent is selected from mannitol, sorbitol, calcium hydrogen phosphate dihydrate, anhydrous dicalcium phosphate, and tribasic calcium phosphate, or any mixture thereof. In some embodiments, the binder is selected from hydroxypropylcellulose, alginic acid, sodium carboxymethylcellulose, copovidone, and methylcellulose, or any mixture thereof. In some embodiments, the disintegrant is selected from sodium starch glycolate, croscarmellose sodium, and crospovidone, or any mixture thereof. In some embodiments, the lubricant is selected from magnesium stearate, stearic acid, palmitic acid, calcium stearate, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol, and sodium stearyl fumarate.

  In some embodiments of all aspects, the pharmaceutical composition comprising ticagrelor and a pharmaceutically acceptable carrier is a bulking agent present in an amount of 20% to 70% by weight, an amount of 3% to 6% by weight. And a disintegrant present in an amount of 2% to 6% by weight, and a lubricant present in an amount of 0.5% to 1% by weight.

  In some embodiments of all aspects, the pharmaceutical composition comprising ticagrelor and a pharmaceutically acceptable carrier is a mixture of mannitol and dicalcium phosphate present in an amount of 20% to 70% by weight, 3% Further comprising hydroxypropylcellulose present in an amount of -6% by weight, sodium starch glycolate present in an amount of 2% -6% by weight, and magnesium stearate present in an amount of 0.5% -1% by weight. Become.

8 depicts an integrated criteria schematic for clinical trial reports in the PEGASUS-TIMI 54 study. Kaplan-Meier rate of cardiovascular mortality, myocardial infarction, and stroke (Panel A), hazard ratios of each dose and both pooled doses and major over 3 years in the PEGASUS-TIMI 54 study per treatment assignment Depicts endpoint rates and individual components (panel B). Kaplan-Meier rate of cardiovascular mortality, myocardial infarction, and stroke (Panel A), hazard ratios of each dose and both pooled doses and major over 3 years in the PEGASUS-TIMI 54 study per treatment assignment Depicts endpoint rates and individual components (panel B). Describes Kaplan-Meier rates of cardiovascular death, myocardial infarction, and stroke over 3 years in the PEGASUS-TIMI 54 study by treatment assignment. 2 depicts a twice-daily primary efficacy endpoint subgroup analysis of ticagrelor 60 mg in the PEGASUS-TIMI 54 study. Depicts the primary efficacy endpoint subgroup analysis in the PEGASUS-TIMI 54 study. Depicts the primary efficacy endpoint subgroup analysis in the PEGASUS-TIMI 54 study. 2 depicts a twice-daily primary efficacy endpoint subgroup analysis of ticagrelor 60 mg in the PEGASUS-TIMI 54 study. The percentage of patients still in treatment in the safety analysis set of the PEGASUS-TIMI 54 study is depicted over time. PEGASUS-TIMI 54 depicts TIMI major bleeding in a subgroup under study. PEGASUS-TIMI 54 depicts TIMI major bleeding in a subgroup under study. PEGASUS-TIMI 54 depicts TIMI major bleeding in a subgroup under study. Describe Kaplan-Meier estimates of time to early permanent discontinuation of study drug due to bleeding based on a safety analysis set. Estimate the predicted probability of cardiovascular death, myocardial infarction, or stroke event and predicted probability of a TIMI major bleeding event within 3 years using a final dose exposure response model stratified by treatment group Depict. The final exposure response analysis data set is used to depict a composite endpoint with / without cardiovascular death, myocardial infarction, and stroke events versus exposure. The final exposure response analysis data set is used to depict TIMI major bleeding events / events versus exposure. Depicts the distribution of cardiovascular death, myocardial infarction, and stroke event time stratified by dose. 8 depicts the distribution of TIMI major bleeding event times stratified by dose. Depicts Kaplan-Meier estimates for patients without TIMI major bleeding events, stratified by dose, versus time. Depicts events occurring or prevented per 1000 patients treated for 3 years in the twice daily treatment group of ticagrelor 60 mg for various safety and efficacy endpoints in the PEGASUS-TIMI 54 study To do. Describes events that occurred or prevented per 1000 patients treated for 3 years in the twice daily treatment group of ticagrelor 90 mg for various safety and efficacy endpoints in the PEGASUS-TIMI 54 study To do. Describes Kaplan-Meier rates of compound endpoints of cardiovascular death, myocardial infarction, or stroke at 90 and 3 years in patients randomized to placebo versus time from P2Y ₁₂ inhibitor withdrawal . 3 depicts the 3-year cardiovascular death, myocardial infarction, or stroke hazard ratio in the PEGASUS-TIMI 54 study versus time from P2Y ₁₂ inhibitor withdrawal to randomization. In patients who discontinued P2Y ₁₂ inhibitor therapy after (A) 30 days from randomization, (B) 30 days to 1 year, and (C) more than 1 year, compared to placebo, Ticagrelor 90 mg twice a day (bid twice), ticagrelor 60 mg twice a day (bid twice), 3 years of cardiovascular death, myocardial infarction, or stroke Describe Kaplan-Meier rate. P2Y12 inhibitor therapy was discontinued within 30 days of randomization, stratified by accredited myocardial infarction for 24 months prior to randomization (left) and ≧ 24 months prior to randomization (right) 8 depicts Kaplan-Meier rates of combined endpoints of cardiovascular death, myocardial infarction, or stroke at 3 years with pooled ticagrelor dose (purple) compared to placebo in patients. Per treatment (pooled ticagrelor dose compared to placebo), first 90 days (left) and 90 days to 3 years as a landmark in patients who ceased P2Y ₁₂ inhibition ≦ 30 days from randomization Delineate Kaplan-Meier rates for composite endpoints of (right) cardiovascular death, myocardial infarction, or stroke. Ticagrelor 90 mg twice daily (bid twice daily) (red), ticagrelor 60 mg twice daily twice (bid twice daily) compared to placebo, versus time from P2Y ₁₂ inhibitor withdrawal ) (Blue) and TIMI major bleeding at year 3 with both pooled doses (purple). In patients who discontinued the P2Y ₁₂ inhibitor therapy within 30 days, placebo (green) as compared to the Chikagureroru 90mg 1 twice a day twice a day (bid twice daily) (red), twice a day Chikagureroru 60mg 1 Depicts third year TIMI major bleeding by bid twice (blue).

  In the usage of this specification, the following definitions shall apply unless otherwise specified.

  As used herein, the term “solid dosage form” generally refers to a pharmaceutical composition comprising capsules, tablets, pills, powders, and granules when used in an oral mode of administration. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier, which may also be referred to as an excipient.

  As used herein, “excipient” or “pharmaceutically acceptable carrier” includes functional and non-functional ingredients in a pharmaceutical composition.

  As used herein, a “disintegrant” is an excipient that hydrates the pharmaceutical composition and aids tablet dispersion. As used herein, a “diluent” or “bulking agent” is an excipient that adds bulk to a pharmaceutical composition.

  As used herein, a “surfactant” is an excipient that imparts enhanced solubility and / or wettability to a pharmaceutical composition.

  As used herein, a “binder” is an excipient that imparts enhanced adhesion or tensile strength (eg, hardness) to a pharmaceutical composition.

  As used herein, a “glue enhancer” is an excipient that imparts enhanced fluidity to a pharmaceutical composition.

  As used herein, a “colorant” is an excipient that imparts a desired color to a pharmaceutical composition. Examples of colorants include commercially available dyes such as FD & C Blue No. 1 aluminum lake, FD & C Blue No. 2, other FD & C blue colorants, titanium dioxide, iron oxide, and / or combinations thereof. In one embodiment, the pharmaceutical composition provided by the present disclosure is purple.

  As used herein, a “lubricant” is an excipient added to a pharmaceutical composition that is compressed into a tablet. Lubricants help compress the granules into tablets and eject the pharmaceutical composition tablets from the die press.

As used herein, a “P2Y ₁₂ receptor antagonist” is an antiplatelet agent that inhibits the function of the G protein-coupled receptor P2Y ₁₂ at least to some extent. Examples of P2Y ₁₂ receptor antagonists include clopidogrel, prasugrel, ticlopidine, ticagrelor, cangrelor, and erinogrel.

As used herein, an “adenosine diphosphate receptor inhibitor”, also referred to as an “ADP receptor blocker” or “ADP receptor block”, refers to some or all types of adenosine diphosphate receptors. It is an antiplatelet agent that inhibits body (ie, P2Y receptor) function at least to some extent. “Adenosine diphosphate receptor inhibitor”, “ADP receptor blocker”, “ADP receptor block”, and “P2Y ₁₂ receptor antagonist” are used interchangeably herein.

  As used herein, a “net clinical benefit” or “risk benefit profile” is from randomization to the first occurrence of any event from a combination of cardiovascular death, myocardial infarction, stroke, or TIMI major bleeding. It's time.

  As used herein, “irreversible harm” is the time from randomization to the first occurrence of any event from a combination of cardiovascular death, myocardial infarction, stroke, intracranial or lethal bleeding. is there.

  As used herein, a “risk factor” is a demographic factor that affects the underlying risk of an event, independent of any medication.

  As used herein, a “covariate” is a demographic factor that modifies the effect of drug therapy after the effects of risk factors have already been taken into account.

  As used herein, “absolute risk reduction” is the difference in risk of outcome in a treatment group compared to a control or placebo group.

  As used herein, “relative risk reduction” is the absolute risk reduction (also referred to as the outcome rate) divided by the risk of outcome in the comparison or placebo treatment group.

  As used herein, “statistically significant reduction in the rate of cardiovascular mortality, myocardial infarction, or stroke” is a dosage regimen in which a daily maintenance dose of 75-150 mg aspirin alone is administered to a patient. The reduction in the rate of cardiovascular death, myocardial infarction, or stroke of the disclosed method compared to is statistically significant for at least one of the relative risk reduction or hazard ratio statistical metrics Means that. Official statistical tests included cardiovascular mortality and total mortality endpoints, as well as combined endpoints for cardiovascular mortality, myocardial infarction, and stroke. The established limit of statistical significance in the official statistical test, taking into account an interim analysis of two doses of ticagrelor and multiple tests, was p <0.02598. All other p values listed herein for exploratory endpoints should be considered nominal because p values are not targeted with respect to multiplicity. In some embodiments, a statistically significant decrease in the rate of cardiovascular death, myocardial infarction, or stroke is characterized by a p-value of less than 0.026 for one of the aforementioned statistical metrics. Attached. In some other embodiments, a statistically significant decrease in the rate of cardiovascular death, myocardial infarction, or stroke is a p-value less than 0.01 for one of the aforementioned statistical metrics. Is characterized by In some embodiments, a statistically significant decrease in the rate of cardiovascular death, myocardial infarction, or stroke is characterized by a p-value less than 0.001 for one of the aforementioned statistical metrics. Attached.

  As used herein, a “nominally significant” exploratory endpoint is characterized by a p-value of less than 0.05.

  As used herein, “Kaplan-Meier rate” or “Kaplan-Meier estimate” refers to the probability of an event or outcome occurring at regular intervals calculated by the Kaplan-Meier method. For more information on Kaplan-Meier analysis and survival statistics, see Rich, Jason T. et al. , Et al. “A practical guide to understanding Kaplan-Meier curves.” Ophthalmology-Head and Neck Surgery 143.3 (2010): 331-336 and Jager, Kitty J., et al. , Et al. "The analysis of survival data: the Kaplan-Meier method." Kidney international 74.5 (2008): 560-565.

  As used herein, “hazard ratio” means the ratio of a hazard rate for a particular event or outcome in an experimental treatment group compared to a comparative treatment group. Hazard ratio measures how often a particular event or outcome occurs in an experimental treatment group over time compared to a comparative treatment group. A hazard ratio of 1 means that there is no difference in event frequency between the experimental treatment group and the comparative treatment group. A hazard ratio greater than 1 means that events or outcomes occurred more frequently in the experimental treatment group compared to the comparative treatment group. A hazard ratio of less than 1 means that an event or outcome occurred less frequently in the experimental treatment group compared to the comparative treatment group.

  As used herein, “Necessary Treatment Number” (NNT) is the number of patients that must follow a treatment plan over a specified period of time to achieve one desired therapy outcome or endpoint.

  As used herein, “Necessary Harmful Number” (NTH) is the number of patients that must follow a treatment plan over a specified period of time to observe an adverse event.

  As used herein, “cardiovascular death” refers to sudden cardiac death, death from acute myocardial infarction, death from heart failure, death from cerebrovascular events, and other cardiovascular causes (ie, pulmonary embolism, aorta Disease, death due to cardiovascular intervention), and death without a well-documented non-cardiovascular cause.

  As used herein, “acute coronary syndrome” refers to a condition in which the blood supplied to the myocardium suddenly stops, ie, heart failure or unstable angina. Acute coronary syndrome may be accompanied by a sudden complete or transient blockage of blood flow to the heart.

  As used herein, “coronary heart disease death” (CHD death) refers to a subset of death from sudden cardiac death, death from acute myocardial infarction, and other cardiovascular causes secondary to coronary reconstruction procedures. To do.

As used herein, “myocardial infarction” (MI) was diagnosed based on the definition of Universal Myocardial Inflation published by Thygene et al in 2007. The terms “myocardial infarction”, “myocardial infarction”, “idiopathic myocardial infarction”, and “idiopathic MI” are used interchangeably herein. Myocardial infarction is a cardiac biomarker, preferably troponin, in which at least one value exceeds the 99 th percentile of the upper reference limit (URL) in addition to evidence of myocardial ischemia with at least one of the following myocardial ischemic symptoms Diagnosed based on detection of elevation and / or decline in:
ECG changes that are signs of new ischemia (ST segment, T wave, or new left leg block); occurrence of pathological Q wave on ECG; imaging evidence of new loss of viable myocardium or new local cardiac wall motion abnormalities;
Sudden anticipation, often with symptoms suggesting myocardial ischemia, with cardiac arrest and possibly new ST elevation or new LBBB, and / or new thrombus evidence from coronary angiography and / or autopsy Unwanted heart death, but death occurs before a blood sample is available or before the appearance of a cardiac biomarker in the blood;
PCI-related myocardial infarction: rise to 99th percentile of URL of cardiac biomarker N3x within 48 hours after PCI;
CABG-related myocardial infarction: 99th percentile value of cardiac biomarker N5x URL within 72 hours after CABG plus new pathological Q wave or new LBBB, or angiographically demonstrated new graft or natural Either coronary artery occlusion or imaging evidence of viable myocardial loss;
Asymptomatic myocardial infarction based on ECG or imaging findings; or pathological findings of acute myocardial infarction otherwise not meeting the above definition.

  As used herein, patients with “history of myocardial infarction” or “history of idiopathic myocardial infarction” are diagnosed based on the definition of Universal Myocardial Infarction published by Thygene et al in 2007. Refers to a patient who has experienced at least one myocardial infarction. For example, as mentioned herein, a patient with acute coronary syndrome (ACS) is also considered a patient with a history of myocardial infarction.

  As used herein, “stroke” means an acute onset of neurological dysfunction resulting from a central nervous system vascular cause.

  As used herein, “primary ischemic stroke” means an acute attack of regional brain, spinal cord, or retinal dysfunction caused by an infarction of central nervous system tissue and demonstrated by imaging.

  As used herein, “primary hemorrhagic stroke” refers to an acute onset caused by atraumatic intracerebral parenchyma, intracerebroventricular, or subarachnoid hemorrhage, as demonstrated by neuroimaging or autopsy. means.

  As used herein, “TIMI major bleeding” refers to at least one of the following: intracranial bleeding; clinically obvious signs of bleeding with hemoglobin (Hgb) drop of ≧ 5 g / dL (or hemoglobin is not available) ≥15% hematocrit reduction); or lethal bleeding (bleeding event that resulted in direct death within 7 days).

  As used herein, “other TIMI major bleeding events” refers to major TIMI bleeding events other than intracranial or lethal bleeding.

  As used herein, “TIMI microhemorrhage” is accompanied by a decrease in Hgb from 3 to b 5 g / dL (or a decrease in hematocrit from 9 to less than 15% if hemoglobin is not available). And any clinically obvious signs of bleeding.

  As used herein, a “safety analysis set” refers to all patients who received at least one dose of randomized ticagrelor or placebo, and patients whose post-administration data are available are safe Included in the sex analysis population. Any mistreated patient (eg, randomized to ticagrelor but actually administered a placebo) is accounted for in the actual treatment group.

  As used herein, “Efficacy Analysis Set”, “Treatment Intent Analysis Set”, and “Complete Analysis Set” are all randomized regardless of patient protocol compliance and continued participation in the trial. Refers to the patient. Patients were analyzed according to randomized study drug, regardless of whether events occurred before or after study drug interruption.

  As used herein, “about” or “approximately” means within 20%, within 10%, and even within 5% of a given value or range.

  As used herein, “baseline” refers to a “dosing regimen in which a daily maintenance dose of 75-150 mg of aspirin alone is administered to a patient”. “Baseline” and “dosage regimen in which a daily maintenance dose of 75-150 mg of aspirin alone is administered to a patient” may be used interchangeably herein. Endpoints in the PEGASUS-TIMI 54 study (ie, reduced relative risk of combined endpoints for cardiovascular mortality, myocardial infarction, or stroke) were assessed for two doses of ticagrelor compared to baseline.

Example: PEGASUS-TIMI 54 (PEGASUS)
The PEGASUS-TIMI 54 trial (also referred to herein as the PEGASUS trial or PEGASUS study) is a randomized, double-blind, placebo that enrolled more than 21,000 patients at 1,161 centers in 31 countries. It was a control multinational clinical trial. The protocol was approved by the relevant ethics committee at all participating institutions. In the United States, ClinicalTrials. The gov number, NCT01225562, was assigned. Results from the PEGASUS test are reported in Bonaca, Marc P., et al. , Et al. “Long-term use of ticaggregor in potential with prior mycardial information.” New England Journal of Medicine 372.19 (2015): 1791-1800.

Eligible patients had a history of idiopathic myocardial infarction from 1 to 3 years prior to enrollment and one of the following additional high-risk characteristics: age 65 years and older; diabetes requiring drug therapy; Idiopathic myocardial infarction; chronic renal dysfunction, defined as multivascular coronary artery disease or estimated creatinine clearance of less than 60 mL / min. During the trial period, P2Y ₁₂ receptor antagonists, dipyridamole, cilostazol, or if there is planned the use of anticoagulants, or patients requiring dialysis, bleeding disorders, ischemic stroke history, intracranial hemorrhage, tumor, Patients were ineligible if they had vascular abnormalities or recent gastrointestinal bleeding or major surgery. Patients could be randomized regardless of the course of previous adenosine diphosphate (ADP) receptor blocker therapy or treatment.

  The full eligibility criteria have been published previously (hereinafter referred to as Bonaca, Bonaca MP, Bhatt DL, Braunwald E, et al. Designation and relational fortending tentatives tentatives in the world. Compared to Placebo on a Background of Asspirin-Thrombolysis in Myocardial information 54 (PEGASUS-TIMI 54) trial. Am Heart J 2014; 167: 437, e. Parts related to sexual criteria are incorporated herein by reference. A written consent form was obtained from all patients. The inclusion / exclusion criteria for the PEGASUS study are shown in Table 2. 3. The majority of patients enrolled in the PEGASUS trial (89.1%) have received prior treatment with adenosine diphosphate receptor blockers; most commonly clopidogrel (83.7%); 4% had received prasugrel, 0.5% ticlopidine, and 0.4% ticagrelor (Table 3).

  Eligible patients were randomized at a 1: 1: 1 ratio and received ticagrelor 90 mg orally twice daily, ticagrelor 60 mg orally twice daily, or placebo. Randomization was performed using a central computer phone or web-based system and the assignment was double blind. The mean time from certified myocardial infarction to randomization in the trial was 21.8 months, and the majority of patients (60.7%) had certified myocardial infarction in the 1-2 years prior to randomization.

As previously published, if a patient develops an indication of P2Y ₁₂ receptor blockade, the modified study treatment option (blinded double dummy ticagrelor or clopidogrel) for use by the investigator ) Was provided (see Bonaca). The modified treatment option was used by less than 4% of patients during the trial. Patients undergoing elective non-cardiovascular surgery were advised to discontinue study treatment 5 days prior to surgery and resume when deemed appropriate by the treating physician. The protocol also defined discontinuation criteria for temporary and permanent discontinuation of treatment with ticagrelor (Table 4).

  All patients enrolled in the PEGASUS study were instructed to take open-label aspirin at a dose of 75-150 mg daily. Because the study population was stable, the initial loading dose of ticagrelor was not administered.

  The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary endpoints were cardiovascular mortality and total mortality. Secondary endpoint analysis started in a cardiovascular death and then progressed in a hierarchical fashion to death from any cause. Additional endpoints listed below were evaluated on an exploratory basis. Exploratory efficacy endpoints included coronary heart disease mortality instead of cardiovascular mortality, and additional endpoints, emergency coronary artery reconstruction, unstable angina, and transient ischemic stroke . The primary safety endpoint was TIMI major bleeding. Other safety endpoints included intracranial hemorrhage (ICH) and lethal bleeding. Endpoint definitions have been published previously (see Bonaca). A central clinical event committee whose members were unaware of the treatment assignment determined all efficacy endpoints and bleeding occurrence.

  Provided approximately 90% power to 20% relative risk reduction with 90 mg twice daily dose and 19% relative risk reduction with 60 mg twice daily dose when each dose was individually compared to placebo A total of 1360 major endpoint events were required to provide 83% power. The primary efficacy analysis is performed based on treatment intent and is the time from randomization to event analysis for the first occurrence of any of the primary composite endpoints of vascular death, myocardial infarction, or stroke, Each of the two doses was individually compared to placebo. Secondary endpoint analysis proceeded hierarchically starting from CV death. Exploratory analysis of both combined doses compared to placebo was pre-designated.

  The safety analysis included all randomized patients who received at least one dose of study drug and for whom post-dose data was available. On the first day of the pre-designated common study, patient follow-up was discontinued when consent was withdrawn or when the final clinical event was evaluated. Safety was analyzed as on-treatment, including all events that occurred after the first dose and within 7 days of the last dose of study drug. To suppress the overall first-class error, α is allocated to each comparison of ticagrelor dose and placebo (using a 0.5 correlation between test statistics), using the Haybittle-Peto approach, Taking into account the interim efficacy analysis performed by the Independent Data Monitoring Committee, a significance level of 0.026 was provided, which is an indicator of statistical significance. Event rates are expressed as Kaplan-Meier estimates of cumulative incidence. Hazard ratios and 95% confidence intervals were generated using the Cox proportional hazards model and all reported P values were two-sided. Because clinical trials are conducted under widely varying conditions, the rate of adverse reactions observed in a clinical trial cannot be directly compared to the rate in another clinical trial of a drug and reflects the actual observed rate You don't have to.

  Between October 2010 and April 2013, a total of 21,162 patients were randomized. Trial sample size assumes a 3.5% annual event rate for the primary endpoint in the placebo group, based on previous studies in similar populations, with 90 mg ticagrelor treated twice daily compared to the placebo-treated group It was determined assuming a target relative risk reduction of 20% in the group and approximately 19% for the twice daily dose of ticagrelor 60 mg. Patient baseline characteristics were well balanced between experimental and comparative placebo treatment groups (Tables 5 and 6).

  The mean (SD) age was 65 years (8), and almost one quarter of the patients were female and nearly one third had diabetes. Patients were mainly white (87%) and had received previous aspirin treatment. The safety analysis population was mainly white (86.7%). 12.1% of patients enrolled in PEGASUS are Hispanic or Latino, blacks (1.7%), Asians (10.7%), and other races (0.9%) Participated in the trial. The median time from certified myocardial infarction to randomization was 1.7 years (IQR 1.0-2.0), and 54% of certified events were ST segment elevated myocardial infarction. Most patients had a history of percutaneous coronary intervention (PCI) (83%) and multivascular coronary artery disease (59%). For additional predefined atherothrombotic risk factors, 54.4% of patients are> 65 years old, 28.5% have diabetes requiring medication, and 16.5% have a second Has a history of previous presumed idiopathic MI (≥1 year prior to randomization), 59.3% have a history of angiographic evidence of multivascular CAD, and 5.9% have chronic non-terminal kidney Had dysfunction (reported by investigator). 47.8% of patients had more than one risk factor for atherothrombosis and 14.6% had more than two risk factors. The randomized treatment group was balanced with respect to these predefined atherothrombotic risk factors.

  Patients were treated well according to current guidelines (Table 7) (Fihn SD, Gardin JM, Abrams J, et al. 2012 "ACCF / AHA / ACP / AATS / PCNA / SCAI / STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation / American Heart Association task force on practice guidelines, and the American College of Physic ans, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons "Circulation 2012; 126:. e354-471, and the Task Force Members, Montalescot G, Sechtem U, et al. “2013 ESC guidelines on the management of stable coronary disease: the Tas k Force on the management of stable coronary arterial disease of the European Society of Cardiology. "Eur Heart J 2013; 34: 2949-3003).

  Almost all patients (95.7%) received aspirin at a dose of 75 mg to 100 mg. A small number of patients (2.7%) took more than 100 mg of aspirin, and a very small number of patients (<0.1%, N = 97) received 75-150 mg required by the PEGASUS-TIMI 54 study protocol. Taking more or less than the daily maintenance dose of aspirin. As expected, doses of 75-81 mg and 100 mg of aspirin dominated (48.9% and 48.3%, respectively) due to prescribing practices in the United States and elsewhere. A maintenance dose of aspirin above 100 mg has been shown in the PLATO study to reduce the efficacy of ticagrelor in patients with acute coronary syndrome.

  20,942 patients (99.0%) received at least one dose of study drug. The percentage of patients who discontinued treatment in each treatment group during the study duration was 32.0%, 28.7%, and 21.4% in the ticagrelor 90 mg, ticagrelor 60 mg, and placebo treatment groups, respectively. (P <0.001 at each dose compared to placebo). Of patients receiving study drug, compliance (defined as taking ≧ 80% of pills administered during treatment) was 79% in the 90 mg ticagrelor, 60 mg ticagrelor, and placebo treatment groups, respectively. 80% and 82%.

  The intermediate duration of follow-up was 33 months (IQR 28-37), resulting in follow-up of 55,266 patient years. Confirmation of the primary endpoint was completed in 98.8% of possible patient year follow-up. Details of patient treatment are described in FIG. In the experimental group, compared to placebo, both doses of ticagrelor significantly reduced the primary endpoint of cardiovascular death, myocardial infarction, and stroke, and the Kaplan-Meier rate at 3 years was higher in the ticagrelor 90 mg treatment group. 7.85%, 7.77% in ticagrelor 60 mg treatment group, 9.04% in placebo treatment group (HR of 90 mg ticagrelor versus placebo 0.85 is 95% CI 0.75-0.96, P = 0.0080; HR of 60 mg of ticagrelor versus placebo 0.84, 95% CI 0.74 to 0.95, P = 0.0043) (Figure 2A, Figure 3). Each of the major endpoint components of cardiovascular death, myocardial infarction, and stroke contributed to a decline in the major composite endpoint. Based on treatment intention data (ie, regardless of study drug discontinuation), if 10,000 patients were started treatment with ticagrelor versus placebo, ticagrelor 90 mg twice daily and Ticagrelor 60 mg twice a day prevents 40 and 42 ischemic events, respectively. The effects of ticagrelor on each of the primary endpoint components are highly consistent (Figure 2B). Similarly, there was a numerical decrease in the combined rate of coronary heart disease death, myocardial infarction, or stroke at both ticagrelor doses compared to placebo (18% RRR, HR0 at 90 mg twice daily). .82 (95% CI 0.72, 0.93), p = 0.016, ticagrelor 60 mg twice a day, 17% RRR, HR 0.83 (95% CI 0.73, 0.94), p = 0.0033). Furthermore, there was a numerical reduction in the rate of coronary stent thrombosis at both doses of ticagrelor compared to placebo (36% RRR, HR0.64 (95% CI at 90 mg of ticagrelor twice daily). 0.41, 1.00), p = 0.0499, ticagrelor 60 mg twice a day, 18% RRR, HR 0.82 (95% CI 0.54, 1.23), p = 0.3328) . An analysis of the time to first stent thrombosis in each treatment group is shown in Table 7. There was a trend towards a numerical decline in cardiovascular mortality due to ticagrelor, but the effect was not statistically significant. Compared to placebo, the difference in mortality due to any cause was not statistically significant at any dose of ticagrelor (Table 8). The frequency of death (including bleeding) was 4.8% (n = 333), 4.2% (n = 33) for ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, and placebo, respectively. 290), and 4.7% (n = 329). When bleeding events were ruled out, the frequency of death was 4.4% (n = 304), 3.9% for ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, and placebo treatment group, respectively. (N = 274) and 4.4% (n = 309). Of note, PEGASUS was capable of detecting changes in the major composite endpoints of CV death, MI or stroke only. This trial was not capable of detecting changes in cardiovascular mortality or overall mortality. Except for the cardiovascular death endpoint, total mortality endpoint, and major composite endpoint of cardiovascular death, myocardial infarction, or stroke, the P values listed in Table 8 are targeted for multiplicity. Should be considered nominal. Other predesignated efficacy endpoints, including hospitalizations for unstable angina and transient ischemic attacks, are rare in all treatment groups (<1% at 3 years) Tables 9 and 10 show. There was no significant difference in the rate of emergency vascular reconstruction, hospitalization for unstable angina, or transient ischemic attacks compared to placebo at either ticagrelor dose (Table 9).

  Both doses are key composites across major subgroups including age, gender, index myocardial infarction type, time from certified myocardial infarction, diabetes, aspirin dose, history of percutaneous intervention, and randomized areas There was no apparent heterogeneity in the efficacy of ticagrelor on the endpoint rate (Figure 4). Additional subgroups are shown in FIGS. 5, 6 and 7, and efficacy data for ticagrelor stratified by aspirin dose are shown in Table 11.

  In the third year, the absolute risk reduction of the treatment group (ticagrelor plus aspirin) compared to aspirin alone was 1.27% in the ticagrelor 60 mg twice daily treatment group and 1.90 in the 90 mg twice daily treatment group. 19%. The relative risk reduction (RRR) of the composite endpoint of cardiovascular disease, myocardial infarction, or stroke on days 1-360 (17% RRR) and on and after day 361 (16% RRR), compared to placebo, It was similar in the twice daily treatment group of ticagrelor 60 mg. Furthermore, the hazard ratio of the composite endpoint of cardiovascular disease, myocardial infarction, or stroke on days 1-360 (0.83) and on and after day 361 (0.84), compared to the placebo treatment group, It was similar in the twice daily treatment group of ticagrelor 60 mg (Table 12). By the Kaplan-Meier plot of cardiovascular death, myocardial infarction, and stroke over 3 years, the ticagrelor treatment group curve begins to separate from the placebo treatment curve following randomization and continues throughout the trial As demonstrated (FIG. 2A, FIG. 3), the excellent therapeutic effect of ticagrelor was consistent throughout the trial.

  Patients in the twice daily treatment group of ticagrelor 60 mg received study drug for up to 48 months (FIG. 8). In the ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, and placebo treatment groups, the mean total duration of exposure to study drug (from first to last dose) was 23.9, 25.3, and 27.3 months; the median overall duration of exposure was 28.3, 29.4, and 30.4 months, respectively. In both ticagrelor treatment groups, a higher percentage of patients discontinued study medication early and permanently compared to the placebo treatment group, resulting in lower mean exposure and median overall duration in the ticagrelor treatment group . The excellent therapeutic effect of ticagrelor over time suggests that it may be appropriate to continue treatment with ticagrelor as long as the patient remains at high risk for atherothrombotic events.

  The primary safety endpoint for major TIMI bleeding is higher at both doses of ticagrelor compared to placebo, with a 3rd year rate of 2.60% in the twice daily treatment group of ticagrelor 90 mg, 1 in ticagrelor 60 mg 2.30% in the twice daily treatment group and 1.06% in the placebo treatment group (Ticagrelor 90 twice daily vs placebo HR was 2.69, 95% CI 1.96-3.70, p <0.001; TI of ticagrelor 60 twice daily vs placebo is 2.32, 95% CI 1.68-3.21, p <0.001, Table 14), apparent between major subgroups There was no non-uniformity (Figures 9-11).

  The rate of lethal or non-lethal intracranial hemorrhage was not particularly different between treatment groups, ie the difference was minimal (Table 14). The number of fatal bleeding events was low: 0.1% (n = 6), 0.3% (n = 11) in the ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, and placebo treatment groups, respectively. , And 0.3% (n = 12), corresponding to the Kaplan-Meier rate at 36 months. Similarly, the incidence of intracranial hemorrhage was minimal, with 0.6% (n = 29) and 0.6% (90% ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, and placebo treated group, respectively. n = 28) and 0.5% (n = 23) corresponding to the Kaplan-Meier rate at the 36th month. Bleeding leading to TIMI and transfusion was also increased by ticagrelor as compared to placebo (Table 3). Bleeding rates leading to transfusions were 2.4% for ticagrelor 90 mg, 2.1% for ticagrelor 60 mg, and 0.7% for placebo (P <0.001 at each dose compared to placebo).

  “Other major TIMI hemorrhages” are important because of their potential to cause morbidity and increased medical need, while being clinically manageable and causing no irreversible harm.

  Early treatment interruption for bleeding was higher with both ticagrelor doses compared to placebo, 7.8% ticagrelol 90 mg twice daily, 6.2% ticagrelor 60% twice daily, It was 1.5% with placebo (Table 14). FIG. 12 shows Kaplan-Meier estimates 12 of time to early permanent interruption of study drug due to bleeding, based on the safety analysis set. The overall outcome of bleeding events in the PEGASUS-TIMI 54 trial is shown in Table 15.

  However, the ticagrelor treatment group showed a trend towards a lower lethal bleeding rate compared to the placebo treatment group, 6 and 9 in the 90 mg and 60 mg ticagrelor treatment groups compared to the 12 lethal bleeding events in the placebo treatment group, respectively. There were 11 fatal bleeding events. In particular, lethal bleeding event rates for TIMI major bleeding events in each ticagrelor experimental treatment group (6/127 in the 90 mg treatment group, ie about 1/21 and 11/115 in the 60 mg treatment group, ie about 1/10) Is significantly below the placebo comparison treatment group (12/54, ie 1 / 4.5). Overall, the absolute bleeding rate is consistent with that observed in other long-term double antiplatelet therapy trials.

  Dyspnea is more frequent with both doses of ticagrelor, and the 3-year event rate is 18.9% in patients treated twice daily with ticagrelor 90 mg, and patients treated twice daily with 60 mg ticagrelor. 15.8% and 6.4% in placebo-treated patients (P <0.001 at each dose compared to placebo, Table 3). The median duration of resolved dyspnea adverse events was 22, 31, and 49 days in the 90 mg twice daily treatment group of ticagrelor, the twice daily treatment group of ticagrelor 60 mg, and the placebo treatment group, respectively. . The incidence of dyspnea and the intermediate duration of resolved dyspnea adverse events were numerically lower in patients in the ticagrelor 60 mg twice daily treatment group compared to the ticagrelor 90 mg twice daily treatment group . The majority of dyspnea episodes with either ticagrelor dose are characterized as either mild (57%) or moderate (38%) severity, and dyspnea as a serious adverse event in patients receiving ticagrelor It was rare (3-year rate of 0.3%). Regardless of treatment group, the majority of patients with dyspnea adverse events had only one onset. The rate of dyspnea leading to study drug discontinuation was 6.5% ticagrelor 90 mg twice daily, 4.3% ticagrelor 60 mg twice daily, and 0.7% placebo (compared to placebo). P <0.001 at each dose taken, Table 3). A PLATO substudy in which 199 subjects underwent pulmonary function testing, regardless of whether they reported dyspnea, had adverse effects on pulmonary function assessed 1 month or at least 6 months after chronic treatment There were no signs of.

  There were no significant differences in the rate of kidney, liver, bradyarrhythmic, or gout adverse events during the PEGASUS study, and no liver or kidney related problems were identified (Table 14). The frequency of predefined bradyarrhythmias AE was similar across treatment groups. PLATO and PEGASUS excluded patients at high risk for bradycardic events (eg, patients with sinus syndrome, 2 or 3 atrioventricular block, or bradycardia-related syncope and not protected by a pacemaker). Assessment of adverse events possibly related to bradyarrhythmia were dizziness, hypotension and syncope in the twice daily treatment group of ticagrelor 90 mg twice daily and ticagrelor 60 mg compared to the placebo treatment group, It was reported more frequently. In the PEGASUS trial, fainting was reported by 1.2% and 0.9% of patients receiving 60 mg ticagrelor twice daily and placebo, respectively.

  Furthermore, a reversible increase in serum uric acid levels consistent with previous findings was observed during the PEGASUS study. In the PLATO study, serum uric acid levels were baseline in patients receiving 90 mg of ticagrelor twice daily compared to an increase of approximately 0.2 mg / dL from baseline in patients receiving clopidogrel. Increased by approximately 0.6 mg / dL. The difference in serum uric acid levels observed during the PLATO trial disappeared within 30 days of discontinuing treatment. Furthermore, the reports of gout were not different between PLATO treatment groups (0.6% in each group). During the PEGASUS study, it was observed that serum uric acid levels increased by approximately 0.2 mg / dL from baseline in patients receiving ticagrelor 60 mg twice daily. No increase in serum uric acid levels was observed in the placebo-treated group. Gout occurred more commonly in patients in the experimental treatment group (1.5%) than in the placebo treatment group (1.1%), and there was no report of urate nephropathy. Hypotension was compared to the placebo-treated group (0.45 events / 100 patient years), ticagrelor 60 mg twice a day (0.66 events / 100 patients (pt) year) and ticagrelor 90 mg twice a day. (0.66 events / 100 patient years) More commonly appeared in patients in the treatment group.

  In the PEGASUS study, the mean serum uric acid concentration decreased after treatment was discontinued. In addition, in the PEGASUS-TIMI 54 study, serum creatinine levels increased by> 50% in approximately 4% of patients who received 60 mg of ticagrelol twice daily, which was observed in patients in the placebo treatment group. It was equivalent to the increase. There was no evidence that increased serum creatinine in the ticagrelor treatment group was associated with kidney injury. Furthermore, the incidence of kidney-related adverse events was similar for ticagrelor and aspirin alone, regardless of age and baseline renal function. The rates of adverse events and serious adverse events are listed in Table 16. The rate of adverse events that occurred during the PEGASUS study at a rate of 3% or higher is shown in Table 17.

Patients who have had myocardial infarction remain at high risk for ischemic events over time. The results of the PEGASUS clinical trial showed that the addition of the P2Y ₁₂ receptor antagonist ticagrelor to low dose aspirin significantly reduces the risk of cardiovascular death, myocardial infarction or stroke in such patients. The benefits of ticagrelor were consistent across major clinical subgroups and from region to region, consistent across individual lethal and non-lethal major endpoint components, and continued over time.

  Using the results of the PEGASUS clinical trial, an exposure response model was developed for ticagrelor 60 mg twice daily, ticagrelor 90 mg twice daily, and placebo treatment group. Use RF models developed for placebo data to assess the impact of risk factors (RF) associated with the composite endpoint of cardiovascular death, myocardial infarction, and stroke, and the safety endpoint of TIMI major bleeding It was done. The RF model was then used for all treatment groups to assess the hazard associated with each risk factor in patients treated with ticagrelor 60 mg twice daily or ticagrelor 90 mg twice daily. Risk factors included in the analysis included age, serum creatinine, body type index, diabetes, hypertension, peripheral arterial disease, history of more than 2 previous MIs, accredited STEMI events, history of unstable angina, aspirin dose, Race, sex, smoking status, ethnicity, clinical coronary artery bypass graft (CABG), clinical trial PCI, idiopathic bleeding requiring previous hospitalization, and left ventricular disease.

  In addition, possible dose exposure response correlations between plasma exposure to ticagrelor and the combined endpoints of cardiovascular death, myocardial infarction, and stroke and the safety endpoint of TIMI major bleeding, as well as possible dose exposure response correlations Covariate effects were examined using exposure response modeling. FIG. 13 shows the predicted probability of cardiovascular mortality, myocardial infarction, or stroke event within 3 years, and predicted TIMI major bleeding event using a final dose exposure response model stratified by treatment group Shows the probability. The mean predictive probability of placebo, ticagrelor 60 mg twice daily, ticagrelor 90 mg twice daily treatment group events was 8.47%, 6.82%, and 6 for cardiovascular death, myocardial infarction, or stroke events. .74%, 1.02%, 2.46%, and 2.65% for TIMI major bleeding events. FIG. 14 depicts a composite endpoint with / without cardiovascular mortality, myocardial infarction, and stroke events versus exposure using the final exposure response analysis data set, and FIG. A response analysis data set is used to depict TIMI major bleeding events / events versus exposure.

  Cardiovascular death, myocardial infarction, or stroke events on treatment data generated in the PEGASUS-TIMI 54 clinical trial were also described by a parametric time-event model. FIG. 16 shows the distribution of cardiovascular death, myocardial infarction, and stroke event time stratified by dose. Baseline hazard decreases slightly over time and is explained by the Weibull distribution. In describing the effects of RF and drug exposure, a proportional hazard model was assumed.

  Exposure response models developed from PEGASUS study data show similar consistent benefits of ticagrelor across subgroups, increasing the risk of combined endpoints of cardiovascular death, myocardial infarction, or stroke in the placebo-treated group, Eight risk factors have been identified: age (above 65 years, a hazard ratio (HR) of 1.03 per year); serum creatinine (above 87 μmol / L and HR of 1.01 per μmol / L); History of unstable angina (1.41 HR); diabetes (1.58 HR); peripheral arterial disease (1.51 HR); two or more previous MIs (2.04 HR); Hispanic / Latin (1.33 HR); and current smokers (1.43 HR). After considering risk factors, no subgroups were identified that were statistically more or less sensitive to ticagrelor exposure except for the Japanese people.

  Based on the results of the exposure response model, events in Japanese patients were lower compared to the total population (eg, Japanese patients with median exposure in the 60 mg group (606 nM) 0 compared to placebo). .29 HR, 60 mg group (606 nM) Japanese patients with median exposure, 0.83 HR compared to placebo). The risk of lower events observed in Japanese patients may be due to lower fundamental risks, more sensitivity of Japanese patients to ticagrelor exposure, or a combination of both. However, the data for the Japanese population was limited (20 of 901 cases).

The estimated exposure response correlation was flat, suggesting that it was close to the maximum response. The average concentration of ticagrelor at steady state ( _{css, av} ) exposure is a slightly more powerful event predictor compared to the pooled general ticagrelor treatment effects at 60 and 90 mg doses over the tested exposure range. there were.

  Treatment data TIMI hemorrhage in the PEGASUS-TIMI 54 clinical trial was further explained by a parametric time-event model. FIG. 17 shows the distribution of TIMI major bleeding event times stratified by dose. Baseline hazard was constant over time explained by the exponential distribution. In describing the effects of risk factors and drug exposure, a proportional hazard model was assumed. In TIMI major bleeding, only two risk factors were identified: age (risk increased with age of 1.04 HR above 65 years and coronary artery bypass grafting (CABG) (575 HR treatment) Temporary impact for up to 7 days later).

In the PEGASUS trial, patients treated with ticagrelor 60 mg twice daily and ticagrelor 90 mg twice daily are consistent with the safety profile of other commercially available P2Y ₁₂ receptor antagonists compared to placebo patients A higher incidence of TIMI hemorrhage was exhibited. The risk of the event was explained by the log-linear exposure response correlation as it increased with increasing drug exposure (ticagrelor c _{ss, av} ). The estimated relative risk increase compared to placebo at 36 months was 142% and 160% respectively at twice daily ticagrelor 60 and 90 mg, and the increased risk of major TIMI bleeding due to ticagrelor exposure was similar across subgroups. It was consistent. FIG. 18 shows Kaplan-Meier estimates for patients without TIMI major bleeding events, stratified by dose, versus time. None of the subgroups were statistically identified as more or less sensitive to ticagrelor exposure after considering risk factors.

  Age was the only risk factor identified in both the final CV death / myocardial infarction / stroke model as well as the final TIMI major bleeding model. However, the average risk of CV death, myocardial infarction, or stroke was higher for ticagrelor 60 mg twice daily and ticagrelor 90 mg twice daily compared to the placebo-treated group for all compared age groups. Decreased in patients (Table 18). Compared to placebo, ticagrelor 60 mg twice daily reduced the absolute risk of compound endpoints for cardiovascular mortality, myocardial infarction, and stroke at 3 years in patients over 75 years than in patients under 65 years High (2.15% vs. 1.38%). However, the absolute increased risk of major TIMI bleeding at 3 years with ticagrelor (60 mg) compared to placebo was also higher in patients over 75 years than in patients under 65 years (2.38% vs. 1.05%). ).

  Patients who received ticagrelor 60 mg twice daily had a net clinical benefit (time from randomization to the first occurrence of any event from a combination of cardiovascular death, myocardial infarction, stroke, or TIMI major bleeding) ) In the PEGASUS-TIMI 54 study, the relative risk reduction was 5% compared to the placebo-treated group (Table 19). In addition, reduced risk of irreversible harm (time from randomization to the first occurrence of any combination of cardiovascular death, myocardial infarction (MI), stroke, intracranial hemorrhage (ICH), or lethal bleeding) ) Was demonstrated in patients receiving ticagrelor 60 mg twice daily and in patients receiving ticagrelor 90 mg twice daily compared to the placebo-treated group. The PEGASUS trial demonstrated a 12% and 14% reduction in the relative risk of irreversible harm for ticagrelor 90 mg twice daily and ticagrelor 60 mg twice daily compared to the placebo-treated group. FIGS. 19 and 20 depict events per 1000 patients treated in the PEGASUS study for 3 years in the twice daily treatment group of 60 mg ticagrelor and 90 mg ticagrelor, respectively.

  The irreversible harm analysis focused on the events with the most severe consequences and excluded “other TIMI major bleeding events”. As used herein, “other TIMI major bleeding events” refers to major TIMI bleeding events other than intracranial or lethal bleeding. While “other TIMI major bleeding events” are clinically important because they cause morbidity and medical needs, the events are still clinically manageable and do not cause irreversible harm. Excluding the “other TIMI major bleeding events” from the benefit risk assessment is consistent with the approach previously used by the US Food and Drug Administration for other drugs. Based on treatment intention data (ie, regardless of study drug discontinuation), if 10,000 patients were started treatment with ticagrelor versus placebo, ticagrelor 90 mg twice daily and Ticagrelor 60 mg twice daily prevents 41 and 31 annual TIMI major bleeding events, respectively.

  Major composite endpoints for CV death, MI, or stroke; and for individual endpoints of CV death, MI, and stroke, absolute risk reduction compared to placebo was 90 mg of ticagrelor twice daily and 60 mg of ticagrelor Observed twice a day (Table 20). Thus, when benefits are considered for the risk of an irreversible harm event, there is a favorable benefit risk balance for both ticagrelor 90 mg twice a day and ticagrelor 60 mg twice a day compared to placebo. Proven.

There was great uncertainty about the duration of double antiplatelet therapy required for patients with coronary artery disease. For patients with a history of idiopathic myocardial infarction, observations from other studies suggested the benefit of longer periods of more powerful antiplatelet therapy. For example, in a landmark analysis from a study of three major P2Y ₁₂ receptor antagonists (clopidogrel, prasugrel, and ticagrelor) in patients with acute coronary syndrome, months beyond the period immediately following acute coronary syndrome There appeared to be a continuous increase in clinical benefit due to P2Y ₁₂ receptor blockade.

Similarly, in the patient subgroup with previous myocardial infarction from the protease-activated platelet receptor antagonist trial, there appeared to be a continuous increase in clinical benefit beyond the first year of treatment. Of note, however, dedicated trials of long-term prophylaxis with clopidogrel over an aspirin background in a broad patient population with atherosclerotic disease or risk factors did not show a statistically significant benefit. The particular examine subsequent analysis a subset of patients with previous myocardial infarction, but suggested a reduction in the ischemic risk certainly, this is a posteriori, current clinical guidelines, P2Y ₁₂ receptor after one year of myocardial infarction Continue to recommend discontinuing body antagonists.

  The fact that a series of randomized trials has not shown the benefit of long-term double antiplatelet therapy following percutaneous coronary intervention (PCI) (including after ACS) Further contributes to uncertainty about effectiveness. However, these studies were relatively small, with relatively low-risk patients enrolled.

Patients in PEGASUS-TIMI 54, the final _{P2Y 12} from inhibitors Time (days: ≦ 30 days, 31-360,> 360) by being further classified. In the placebo-treated group, patients who discontinued P2Y ₁₂ inhibitor therapy more recently had higher risk factors compared to patients who discontinued> 1 year ago, but still have higher MACE after multivariate adjustment. [≦ 30 days, hazard ratio (HR) _adj 1.47, 95% confidence interval (CI) 1.12 to 1.93, P = 0.005; 30 days to 1 year, HR _adj 1 .28, 95% CI 0.98 to 1.67, P = 0.073) (P tendency = 0.0070) (FIG. 21). The benefits of ticagrelor depend on the time since the last dose, and the HR (95% CI) of ticagrelor (pooled dose) compared to placebo is 0.73 (0.61 to 0.87) for each category. , 0.86 (0.71 to 1.04), and 1.01 (0.80 to 1.27) (P tendency of interaction <0.001) (FIG. 22). FIG. 23 shows ticagrelor 90 mg twice a day compared to placebo in patients who discontinued P2Y12 inhibitor therapy within 30 days, 30 days to 1 year, and beyond 1 year after randomization. FIG. 5 shows Kaplan-Meier curves for cardiovascular death, myocardial infarction, or stroke at 3 years with bid twice daily, bid twice daily with 60 mg of ticagrelor. Benefits in patients interrupted at ≦ 30 days were similar regardless of time from MI (<2 years, HR 0.73, 95% CI 0.60-0.89 vs ≧ 2 years, HR 0. 71, 95% CI 0.50-1.00) (FIG. 24).

Patients enrolled in the PEGASUS study who started or resumed treatment with ticagrelor (60 mg and 90 mg pools) within 30 days after discontinuation of double antiplatelet therapy had a 27% reduction in the risk of subsequent atherothrombotic events (2.2% absolute decrease). Patients enrolled in the PEGASUS study who started or resumed treatment with ticagrelor (60 mg and 90 mg pools) between 31 days and 1 year after discontinuation of double antiplatelet therapy are at risk of developing subsequent atherothrombotic events 14% decrease (1.1% absolute decrease). Patients who started or resumed treatment with ticagrelor more than one year after the withdrawal of the previous double antiplatelet therapy event did not experience a reduced risk of subsequent atherothrombotic events. Thus, the risk reduction of cardiovascular death, myocardial infarction, or stroke in stable patients with previous myocardial infarction is greatest in patients who have more recently discontinued P2Y ₁₂ therapy, with 60 mg ticagrelor twice daily treatment group The patients had hazard ratios of 0.75, 0.82, and 1.06.

  In a subgroup of patients who started or resumed treatment with ticagrelor (60 mg and 90 mg pools) within 30 days following discontinuation of double antiplatelet therapy, the risk reduction for cardiovascular death, myocardial infarction, or stroke was Patient's certified myocardial infarction is less than 2 years prior to randomization (HR 0.73, 95% CI 0.60 to 0.89) or more than 2 years (HR 0.71, 95% CI 0.50 to 1. 00) or not. The benefit of ticagrelor (pooled dose) is the first 90 days after randomization with 0.54 HR (95% CI 0.34-0.86) for both pooled doses, and 90 days It was remarkable after that (HR 0.76, 95% CI 0.63 to 0.92) (FIG. 25). Similar effect doses were seen for the individual primary endpoint components, with a pooled ticagrelor dose HR of 0.78 (95% CI 0.57-1.07 compared to placebo) for cardiovascular death. ), 0.72 for myocardial infarction (95% CI 0.58-0.90) and 0.64 for stroke (95% CI 0.43-0.95).

Baseline characteristics of patients with timing from the last dose of P2Y ₁₂ inhibitor in the PEGASUS study were similar between groups for most features (Table 22). However, patients who discontinued the _{P2Y 12} inhibitor within the past 30 days, temporally closer to the nearest myocardial infarction (median 16 vs. 19 vs. 29 months, P <0.001). They also had more frequent diabetes, multivascular coronary artery disease (CAD), and previous PCIs, and were likely to be randomized in North America.

It should be noted, patients in the placebo treatment group was discontinued P2Y ₁₂ inhibitor within the past 30 days, patients (8.70%), which was interrupted 30 days to 1 year prior to randomization, and one year There was a higher risk of cardiovascular death, myocardial infarction, or stroke (9.91% at 3 years) compared to patients who discontinued beyond (6.91%, P trend 0.0097). On the other hand, TIMI major bleeding in patients randomized to placebo is similar throughout the time bin from P2Y ₁₂ inhibitor withdrawal, with a 3-year rate of less than 30 days, 30 days to 1 year, and 1 year. The excess was 0.7, 1.2, and 0.9%, respectively. After correcting for baseline differences, the hazard ratio for TIMI hemorrhage was 0.51 (95%) for patients who discontinued less than 30 days compared to those who discontinued 0.1 years prior to randomization. CI 0.20 to 1.33, P = 0.17), 0.69 (0.29-1.66, P = 0.41) among patients discontinued 30 days to 1 year ago (group) Overall p trend 0.18).

Benefits of Chikagureroru for long secondary prevention in patients with previous MI and at least one additional risk factor stopped P2Y ₁₂ inhibitor therapy beyond one year showed stable beyond 2 years from MI compared to patients, in patients resumed after continuous or short interrupting P2Y ₁₂ inhibition seemed more pronounced. The increase in bleeding events with ticagrelor was similar regardless of this time interval. For clinicians considering long-term P2Y ₁₂ inhibitor therapy strategies in high-risk patients, these data indicate that post-MI rather than resuming such therapy in patients who remain stable over time It suggests a greater benefit of continuing such therapy without interruption. Table 23 shows the results at month 36 versus time from P2Y ₁₂ withdrawal to randomization.

  The results of PEGASUS-TIMI 54 now support a positively defined evidence base that supports the hypothesis that long-term, more potent platelet inhibition with ticagrelor reduces ischemic events in patients with previous idiopathic myocardial infarction provide.

Related to that is addressed to different questions, it is reported DAPT tested recently, due to the continuation of the double antiplatelet therapy with P2Y ₁₂ receptor blockers on aspirin background, more than 12 months coronary stenting Demonstrated a reduction in non-lethal ischemic events. Notably, patients on DAPT were limited to those without bleeding complications in the preceding 12 months and were randomized to continue or discontinue treatment immediately after the end of this period. Therefore, the trial selected a subset of patients that had recently survived P2Y ₁₂ receptor blockade, which tended to minimize bleeding complications. Furthermore, the increase in adverse cardiovascular events was observed immediately after interruption of the P2Y ₁₂ receptor blockade. (See Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual anti-virus after drug-entry-senting-sents. N Engl J Med 2014 1437; This observation is without interruption in patients whose clinical benefits observed in the PEGASUS trial successfully completed the 1-year process after myocardial infarction, where patients were excluded from their index events and double antiplatelet therapy. This suggests that the benefits that may be achieved during the duration of ticagrelor may be underestimated.

  Ticagrelor, like other antiplatelet agents, can cause serious and sometimes fatal bleeding. Ticagrelor increased bleeding at both doses, including major TIMI bleeding, bleeding leading to transfusions, and bleeding leading to study drug interruption. However, the rate of the most severe bleeding events of intracranial and fatal bleeding was low over the 3-year follow-up and was similar between the ticagrelor and placebo treatment groups. Bleeding with ticagrelor was not different in any of the major subgroups evaluated. However, the trial protocol ruled out patients with recent bleeding, previous stroke, or a need for oral anticoagulant therapy, so the observed long-term ticagrelor safety is more at risk of bleeding It is important to note that it should not be generalized to a group of people. Both doses of ticagrelor also caused dyspnea, which occurred early after initiation of treatment and contributed to a higher treatment interruption rate compared to placebo. The drug interruption rate due to dyspnea seen with ticagrelor in this study was higher than that seen with PLATO. However, this trial enrolls patients with acute coronary syndrome, who are often associated with acute dyspnea in acute illness, and the occurrence of dyspnea may be surprising and therefore leads to interruption In contrast to the more likely and stable patients.

  Dyspnea is unlikely to manifest in patients already tolerated to ticagrelor who have decided to continue treatment for more than a year after myocardial infarction. In addition, drug withdrawal rates in PEGASUS were similar to those observed in other long-term secondary prevention studies, and most of the differences in withdrawal rates between ticagrelor and placebo treatment groups accumulated immediately after randomization. As a result, in clinical practice, if a patient has tolerated ticagrelor for 12 months after myocardial infarction, continuing ticagrelor for more than 12 months may trigger a new onset of dyspnea or further increase the risk of bleeding events It is not expected to increase.

  The two doses of ticagrelor tested achieved a similar magnitude of effectiveness in the treatment intention analysis. However, the rates of bleeding and dyspnea were numerically lower with ticagrelor 60 mg twice daily compared to ticagrelor 90 mg twice daily, with lower treatment interruption rates and better tolerability for the 60 mg dose. Obtained. Thus, in general, a 60 mg dose may provide a more attractive benefit risk and tolerability profile. It should also be noted that both doses were tested for the background of low-dose aspirin recommended for patients with stable ischemic heart disease.

  Addition of 90 mg ticagrelor twice daily or 60 mg twice daily to low-dose aspirin reduces risk of cardiovascular death, myocardial infarction, or stroke in patients with myocardial infarction 1-3 years ago I let you. Ticagrelor increased TIMI major bleeding but did not significantly increase intracranial bleeding. Ticagrelor showed a tendency to at least reduce lethal bleeding. Taking into account the benefit risk profile, coupled with the established benefit of ticagrelor in the context of acute coronary syndrome, these data are for patients with myocardial infarction who are at high risk for cardiovascular events and without major risk factors for bleeding Support the study of continuing ticagrelor for more than one year. Taken together, PLATO and PEGASUS-TIMI 54 clinical trials provide consistent evidence of the benefits that ticagrelor can provide for patients with coronary artery disease in acute and chronic secondary prevention.

Example 2: Ticagrelor 60 mg twice a day provides effective platelet inhibition in patients with myocardial infarction (MI) before h-PEGASUS-TIMI 54 platelet function sub-study The PEGASUS-TIMI 54 test Two doses of ticagrelor were tested for long-term prevention of ischemic events in one patient, 90 mg oral twice daily (bid) and 60 mg twice daily. Compared to placebo as shown in Example 1, both doses reduced the risk of cardiovascular death, myocardial infarction, or stroke in patients who had myocardial infarction 12 to 36 months ago. . The 60 mg twice daily dose pharmacokinetics (PK) and pharmacokinetics had not been previously studied. This substudy aimed to characterize PK and platelet inhibition by ticagrelor 60 mg twice daily versus 90 mg twice daily. 180 patients who received study drug> 4 weeks had blood drawn in the morning before maintenance and 2 hours after dosing. All patients received aspirin. Plasma levels of ticagrelor and active metabolites (AR-C124910XX) were determined. The well-known VerifyNow® P2Y12 assay and light transmittance aggregometry (LTA; ADP 20 uM) were performed. Groups were compared using the Kruskal-Wallis test, allowing significance for P <0.01, allowing multiple group comparisons. Demographic characteristics at randomization generally matched well between the groups (Table 23).

  Ticagrelor demonstrated dose-proportional pharmacokinetics, which was similar in patients and healthy volunteers. Results showed plasma ticagrelor levels approximately 1/3 lower at 60 mg compared to 90 mg (post dose: 448 vs 717 ng / mL; P <0.001). Both doses achieved high levels of platelet inhibition before and after administration, with slightly more variability at 60 mg (Table 24). High platelet reactivity assessed by VerifyNow® (PRU> 208) was rare (3.5%) before administration at 60 mg and absent after administration. Platelet reactivity before and after administration as measured by LTA was numerically lower at 90 mg than at 60 mg, but was not significant. Furthermore, ticagrelor did not significantly affect the measurement of aspirin response, there was no difference in VerifyNow aspirin assay results and no difference in serum thromboxane B2 levels between the placebo group and both ticagrelor groups.

  Ticagrelor 60 mg twice daily achieved high levels of peak and trough platelet inhibition in almost all patients with similar and consistent effects compared to 90 mg twice daily. These results help explain the effectiveness of lower doses of ticagrelor in the PEGASUS-TIMI 54 study.

Other Embodiments Where the meaning of a term in any part of a patent or document incorporated by reference conflicts with the meaning of a term used in this disclosure, the meaning of the term in this disclosure prevails. In one aspect, the present disclosure relates to cardiovascular death, myocardium in a patient in need thereof comprising the step of administering to a patient a pharmaceutical composition comprising 60 mg of ticagrelor twice a day. Provide a method of reducing the rate of infarction or stroke, the patient is also administered a daily maintenance dose of 75-150 mg aspirin; and additionally only a daily maintenance dose of 75-150 mg aspirin is administered to the patient Compared to the dosing regimen, the rate of cardiovascular death, myocardial infarction, or stroke in the patient is reduced.

  In some embodiments, the daily maintenance dose of aspirin is 75 mg to 100 mg.

  In some embodiments, the daily maintenance dose of aspirin is 75 mg to 81 mg.

  In some embodiments, the daily maintenance dose of aspirin is 100 mg.

  In some embodiments, the patient has a history of myocardial infarction.

  In some embodiments, the patient has a history of myocardial infarction as a result of ST segment elevation myocardial infarction.

  In some embodiments, the patient has a history of myocardial infarction for at least 12 months prior to twice daily administration of a pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier.

  In some embodiments, the patient has a history of myocardial infarction between 12 and 36 months prior to twice daily administration of a pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier.

  In some embodiments, the patient has a coronary stent.

  In some embodiments, the patient is also administered lipid lowering therapy.

  In some embodiments, the patient is also administered at least one agent selected from statins, beta blockers, ACEI, or ARB.

  In some embodiments, the patient meets the inclusion criteria for the PEGASUS-TIMI 54 study listed in Table 2.

  In some embodiments, the patient is at least 50 years old. In some further embodiments, the patient is at least 65 years old.

  In some embodiments, the patient has diabetes requiring medication.

  In some embodiments, the patient has a history of evidence of multivascular CAD angiography.

  In some embodiments, the patient has chronic non-end stage renal dysfunction.

  In some embodiments, the patient has more than one atherothrombosis risk factor. In some further embodiments, the patient has more than two atherothrombosis risk factors.

  In some embodiments, the patient is white.

  In some embodiments, the patient is Japanese. In some further embodiments, the patient is Japanese and the method comprises cardiovascular mortality, myocardial infarction, as compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Or, the time to the first composite endpoint of stroke results in a hazard ratio of less than 0.29.

  In some embodiments, the patient has hypertension.

  In some embodiments, the patient has hypercholesterolemia.

  In some embodiments, the patient is a current smoker.

  In some embodiments, the patient has a history of more than one previous myocardial infarction.

  In some embodiments, the patient has peripheral arterial disease.

  In some embodiments, the patient has a history of percutaneous coronary intervention (PCI).

  In some embodiments, the patient has a creatinine clearance of less than 60 mL / min.

  In some embodiments, the patient does not meet any of the exclusion criteria for the PEGASUS-TIMI 54 study listed in Table 2.

  In some embodiments, the patient is not taking dipyridamole or cilostazol.

  In some embodiments, the patient is not taking a potent inducer, inhibitor or substrate of CYP3A.

  In some embodiments, the patient does not have chronic anticoagulation.

  In some embodiments, the patient does not have a known bleeding disorder or coagulopathy.

In some embodiments, the patient is not at increased risk of bleeding for the following reasons:
A history of intracranial hemorrhage at any time,
Central nervous system tumors or intracranial vascular abnormalities (eg, aneurysms, arteriovenous malformations) at any point in time
Intracranial or spinal surgery within 5 years, or Gastrointestinal (GI) bleeding within the past 6 months, or major surgery within 30 days

  In some embodiments, the patient does not have a history of ischemic stroke.

  In some embodiments, the patient is not considered at risk for a bradycardia event.

  In some embodiments, the patient is considered at risk for a bradycardia event but is treated with a long-term pacemaker.

  In some embodiments, the patient has not undergone coronary artery bypass grafting in the last 5 years.

  In some embodiments, the patient does not have a known severe liver disease.

  In some embodiments, the patient has a life expectancy of at least one year.

  In some embodiments, the patient has a history of myocardial infarction as a result of acute coronary syndrome. In some further embodiments, prior to administration, a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier is administered to a patient daily for a portion of 12 months after acute coronary syndrome. It was administered twice. In some further embodiments, prior to administration, a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier is administered to a patient twice a day for 12 months after acute coronary syndrome. It was done. In still some further embodiments, prior to administration, the pharmaceutical composition comprising 90 mg ticagrelor and a pharmaceutically acceptable carrier comprises 180 mg ticagrelor initial loading prior to twice daily administration. A pharmaceutical composition consisting of was administered to a patient.

  In some embodiments, the patient has been previously treated with an ADP receptor blocker. In some further embodiments, the patient has been previously treated with an ADP receptor blocker selected from clopidogrel, prasugrel, ticlodipine, or ticagrelor.

  In some embodiments, the patient's final administration of the ADP receptor blocker occurred less than 7 days prior to administration. In some embodiments, the last dose of the patient's ADP receptor blocker occurred 8 to 90 days prior to administration. In some embodiments, the patient's final administration of the ADP receptor blocker occurred within 30 days prior to administration. In some embodiments, the patient's final administration of the ADP receptor blocker occurred 3-12 months prior to administration. In some embodiments, the patient's final administration of the ADP receptor blocker occurred prior to 12 months of administration.

  In some embodiments, the primary efficacy endpoint of the patient subgroup is consistent with the primary efficacy subgroup analysis shown in FIGS.

  In some embodiments, the patient subgroup TIMI major bleeding is consistent with the TIMI major bleeding subgroup analysis shown in FIGS.

  In some embodiments, the safety and tolerability endpoints are consistent with the data shown in Table 14.

  In some embodiments, the bleeding event matches the data shown in Table 15.

  In some embodiments, adverse events occur at a rate consistent with that disclosed in Tables 16 and 17.

  In some embodiments, the average risk at year 3 for patients under 65 is consistent with the data shown in Table 18.

  In some embodiments, the average risk at 3 years for patients aged 65-75 is consistent with the data shown in Table 18.

  In some embodiments, the average risk at 3 years for patients over 75 years is consistent with the data shown in Table 18.

  In some embodiments, the Kaplan-Meier rate for patients without a TIMI major bleeding event, versus time, matches the curve shown in FIG.

In some embodiments, the safety and efficacy results at year 3 for the time from P2Y ₁₂ inhibitor withdrawal to randomization are consistent with the data shown in Table 22.

  In some embodiments, the method results in platelet reactivity consistent with the data shown in Table 24.

In some embodiments, the method meets at least one of the following efficacy endpoints:
1. The method numerically reduces the composite endpoint rate of cardiovascular mortality, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
2. The method numerically reduces the absolute risk of a combined endpoint of cardiovascular mortality, myocardial infarction, or stroke compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient ;
3. The method poses a relative risk of less than 1 for a composite endpoint of cardiovascular mortality, myocardial infarction, or stroke compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient ;
4). The method numerically measures the Kaplan-Meier rate of combined endpoints of cardiovascular mortality, myocardial infarction, or stroke compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone Reduce;
5). The method is statistically significant for the composite endpoint rate of cardiovascular death, myocardial infarction, or stroke compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to patients Bring about a decline;
6). The method is statistically significant 1 for a composite endpoint of cardiovascular death, myocardial infarction, or stroke compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Results in a relative risk of less than
7). The method results in a Kaplan-Meier rate of approximately 7.8% for a composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years;
8). The method results in a Kaplan-Meier rate of 7.8% for the combined endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years;
9. The method results in a Kaplan-Meier rate of 7.77% for the combined endpoint of cardiovascular death, myocardial infarction, or stroke at year 3;
10. The method results in a hazard ratio of less than 1 for a composite endpoint of cardiovascular mortality, myocardial infarction, or stroke compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient ;
11. The method provides statistics on the time to the first composite endpoint of cardiovascular death, myocardial infarction, or stroke, compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a hazard ratio significantly less than 1;
12 The method measures the percentage of patients with a composite endpoint of cardiovascular death, myocardial infarction, or stroke event as compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. A deteriorating effect;
13. Time to first composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to the patient Results in a hazard ratio of approximately 0.84;
14 Time to first composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to the patient Results in a hazard ratio of 0.84;
15. Time to first composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to the patient Resulting in a hazard ratio of 0.74 to 0.95;
16. Time to first composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to the patient A hazard ratio of 0.74 to 0.95 resulting in a 95% confidence interval;
17. The method approximates the absolute risk of a composite endpoint of cardiovascular mortality, myocardial infarction, or stroke at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. 1.27% reduction;
18. The method reduces the absolute risk of a composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. .27% reduction;
19. The method approximates 17 to 360-day combined endpoints of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. % Relative risk reduction;
20. 17% for a combined endpoint of cardiovascular mortality, myocardial infarction, or stroke between 1 and 360 days compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Reduce the relative risk of
21. Kaplan-Meier rate of compound endpoints of cardiovascular mortality, myocardial infarction, or stroke at 3 years compared to a regimen in which the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to patients Of approximately 1.2%;
22. Kaplan-Meier rate of compound endpoints of cardiovascular mortality, myocardial infarction, or stroke at 3 years compared to a regimen in which the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to patients Of 1.2%;
23. In patients with a combined endpoint event of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Reduce the percentage by approximately 1.3%;
24. In patients with a combined endpoint event of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Reduce the percentage by 1.3%;
25. The method numerically reduces at least one absolute risk of cardiovascular mortality, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
26. The method has a relative risk of less than 1 for at least one of cardiovascular death, myocardial infarction, or stroke, as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about;
27. The method numerically reduces at least one Kaplan-Meier rate of cardiovascular mortality, myocardial infarction, or stroke compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to a patient Let;
28. The method poses a relative risk of less than 1 in the time to the first cardiovascular death event compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
29. The method results in a hazard ratio of less than 1 in the time to the first cardiovascular death event compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
30. The method results in a numerical reduction in the percentage of patients with cardiovascular death events compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
31. The method results in a Kaplan-Meier rate of approximately 2.9% for the third year of cardiovascular death;
32. The method results in a Kaplan-Meier rate of 2.9% for the third year of cardiovascular death;
33. The method reduces the Kaplan-Meier rate of cardiovascular death at year 3 by approximately 0.5% compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
34. The method reduces the Kaplan-Meier rate of cardiovascular mortality at year 3 by 0.5% compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
35. The hazard ratio of the method is approximately 0.83 in time to the first cardiovascular death event in year 3, compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Bring about;
36. The method has a hazard ratio of 0.83 at the time to the first cardiovascular death event in year 3 compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about;
37. Compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, the method is 0.68 to 1.01 at the time to the first cardiovascular death event of the third year. Resulting in a hazard ratio of
38. Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, the method is 0.68 to 1.01 of time to the first cardiovascular death event of the third year Provides a 95% confidence interval for the hazard ratio;
39. The method results in a hazard ratio of less than 1 in the time to the first myocardial infarction event as compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
40. The method poses a relative risk of less than 1 in the time to the first myocardial infarction event, compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
41. The method results in a numerical reduction in the percentage of patients with myocardial infarction events as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patients;
42. The method results in a reduction in the percentage of patients with myocardial infarction events as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
43. The method results in a hazard ratio of approximately 0.84 at the time to the first myocardial infarction event at year 3 compared to a regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient ;
44. The method results in a hazard ratio of 0.84 at the time to the first myocardial infarction event at year 3 compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
45. The method has a hazard of 0.72 to 0.98 at the time to the first myocardial infarction event at year 3 compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Yields a ratio;
46. Hazard ratio of 0.72 to 0.98 of time to first myocardial infarction event at year 3 compared to a dosing regimen where the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to the patient Results in a 95% confidence interval;
47. The method results in a Kaplan-Meier rate of approximately 4.5% for the third year of myocardial infarction;
48. The method results in a Kaplan-Meier rate of 4.5% for the third year of myocardial infarction;
49. The method reduces the Kaplan-Meier rate of myocardial infarction at year 3 by approximately 0.7% compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
50. The method reduces the Kaplan-Meier rate of myocardial infarction at year 3 by 0.7% compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
51. The method results in a hazard ratio of less than 1 in the time to the first stroke event as compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
52. The method poses a relative risk of less than 1 in the time to first stroke compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
53. The method results in a numerical reduction in the percentage of patients with a stroke event compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
54. The method results in a hazard ratio of approximately 0.75 in the time to the first stroke event of the third year compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
55. The method results in a hazard ratio of 0.75 in the time to the first stroke event in year 3 compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
56. The method provides a 0.57-0.98 hazard ratio in the time to the first stroke event in year 3 compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Bring about;
57. The method has a hazard ratio of 0.57 to 0.98 of time to first stroke event in year 3 compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Yields a 95% confidence interval;
58. The method results in a Kaplan-Meier rate of approximately 1.5% for the third year of stroke;
59. The method yields a Kaplan-Meier rate of 1.5% for the third year of stroke;
60. The method reduces the Kaplan-Meier rate of stroke at year 3 by approximately 0.5% compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
61. The method reduces the Kaplan-Meier rate of stroke at year 3 by 0.5% compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
62. The method results in a hazard ratio of less than 1 in the time to the first ischemic stroke event as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
63. The method poses a relative risk of less than 1 in the time to the first ischemic stroke event compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
64. The method results in a numerical reduction in the percentage of patients with an ischemic stroke event as compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
65. The method has a hazard ratio of approximately 0.76 at the time to the first ischemic stroke event at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about;
66. The method results in a hazard ratio of 0.76 in the time to the first ischemic stroke event at year 3 compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient ;
67. Compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient, the method has a 0.56 to 1.02 time to first ischemic stroke event at 3 years. Resulting in a hazard ratio;
68. Hazard of 0.56 to 1.02 of time to first ischemic stroke event at year 3 compared to a dosing regimen where the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to the patient The ratio results in a 95% confidence interval;
69. The method results in a Kaplan-Meier rate of approximately 1.3% for the third year of ischemic stroke;
70. The method results in a Kaplan-Meier rate of 1.3% for the third year of ischemic stroke;
71. The method reduces the Kaplan-Meier rate of ischemic stroke at year 3 by approximately 0.4% compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
72. The method reduces the Kaplan-Meier rate of ischemic stroke at year 3 by 0.4% compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
73. The method results in a hazard ratio of less than 1 in the time to the first coronary heart disease death event as compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
74. The method provides a relative risk of less than 1 in the time to the first coronary heart disease death event compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
75. The method results in a numerical reduction in the percentage of patients with coronary heart disease death events as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
76. The hazard ratio of the method is approximately 0.80 in time to the first coronary heart disease death event in year 3, compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about;
77. The method has a hazard ratio of 0.80 for the time to the first coronary heart disease death event in year 3, compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about;
78. Compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, the method is 0.62 to 1.04 in time to the first coronary heart disease death event in year 3. Resulting in a hazard ratio of
79. Compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method has a 0.62 to 1.04 time to first coronary heart disease death event at year 3 Provides a 95% confidence interval for the hazard ratio;
80. The method results in a Kaplan-Meier rate of approximately 1.7% for the third year of death from coronary heart disease;
81. The method results in a Kaplan-Meier rate of 1.7% for the third year of coronary heart disease death;
82. The method reduces the Kaplan-Meier rate of ischemic stroke at year 3 by approximately 0.4% compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
83. The method reduces the Kaplan-Meier rate of ischemic stroke at year 3 by 0.4% compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
84. The method numerically reduces the composite endpoint rate of coronary heart disease death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
85. The method numerically reduces the absolute risk of a combined endpoint of coronary heart disease mortality, myocardial infarction, or stroke compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone ;
86. The method poses a relative risk of less than 1 for the combined endpoint of coronary heart disease death, myocardial infarction, or stroke, compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient ;
87. The method numerically measures the Kaplan-Meier rate of combined endpoints of coronary heart disease death, myocardial infarction, or stroke compared to a regimen in which a patient is administered a daily maintenance dose of only 75 mg to 150 mg of aspirin. Reduce;
88. The method results in a relative risk reduction of approximately 17% at the composite endpoint of 3 year coronary heart disease death, myocardial infarction, or stroke;
89. The method results in a 17% relative risk reduction at the composite endpoint of 3 year coronary heart disease death, myocardial infarction, or stroke;
90. When the method is compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, the time to the first combined endpoint of coronary heart disease death, myocardial infarction, or stroke is 1 Resulting in a hazard ratio of less than;
91. The method shows the percentage of patients with a composite endpoint of coronary heart disease death, myocardial infarction, or stroke event compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about a decline;
92. Time to first composite endpoint of coronary heart disease death, myocardial infarction, or stroke at year 3 compared to a dosing regimen where the patient is given a daily maintenance dose of 75 mg to 150 mg aspirin alone Results in a hazard ratio of approximately 0.83;
93. Time to first composite endpoint of coronary heart disease death, myocardial infarction, or stroke at year 3 compared to a dosing regimen where the patient is given a daily maintenance dose of 75 mg to 150 mg aspirin alone Results in a hazard ratio of 0.83;
94. Time to first composite endpoint of coronary heart disease death, myocardial infarction, or stroke at year 3 compared to a dosing regimen where the patient is given a daily maintenance dose of 75 mg to 150 mg aspirin alone Resulting in a hazard ratio of 0.73 to 0.94;
95. Time to first composite endpoint of coronary heart disease death, myocardial infarction, or stroke at year 3 compared to a dosing regimen where the patient is given a daily maintenance dose of 75 mg to 150 mg aspirin alone Yields a 95% confidence interval for a hazard ratio of 0.73 to 0.94;
96. The method results in a Kaplan-Meier rate of approximately 7.1% for a composite endpoint of 3 year coronary heart disease death, myocardial infarction, or stroke;
97. The method results in a 7.1% Kaplan-Meier rate at the composite endpoint of 3-year coronary heart disease death, myocardial infarction, or stroke;
98. Kaplan-Meier rate of compound endpoints of coronary heart disease mortality, myocardial infarction, or stroke at year 3 compared to a dosing regimen in which the method is administered to patients with a daily maintenance dose of 75 mg to 150 mg aspirin alone Of approximately 1.2%;
99. Kaplan-Meier rate of compound endpoints of coronary heart disease mortality, myocardial infarction, or stroke at year 3 compared to a dosing regimen in which the method is administered to patients with a daily maintenance dose of 75 mg to 150 mg aspirin alone Of 1.2%;
100. The method numerically reduces the composite endpoint rate of coronary heart disease death or myocardial infarction compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
101. The method numerically reduces the absolute risk of combined endpoints of coronary heart disease mortality or myocardial infarction compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
102. The method poses a relative risk of less than 1 at the combined endpoint of coronary heart disease death or myocardial infarction compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
103. The method numerically reduces the Kaplan-Meier rate at the combined endpoint of coronary heart disease death or myocardial infarction compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
104. Hazard less than 1 in time to first composite endpoint of coronary heart disease death or myocardial infarction, as compared to a dosing regimen wherein a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to a patient Yields a ratio;
105. The method results in a numerical reduction in the percentage of patients with a composite endpoint of coronary heart disease death or myocardial infarction event compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to patients ;
106. Compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, the method is approximately at the time to the first composite endpoint of coronary heart disease death or myocardial infarction at year 3. Resulting in a hazard ratio of 0.84;
107. When the method is compared to a dosing schedule in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient, the time to the first composite endpoint of coronary heart disease death or myocardial infarction at year 3 is 0. Resulting in a hazard ratio of 84;
108. When the method is compared to a dosing schedule in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient, the time to the first composite endpoint of coronary heart disease death or myocardial infarction at year 3 is 0. Resulting in a hazard ratio of .73 to 0.96;
109. Compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method is 0. 0 of time to first composite endpoint of 3 year coronary heart disease death or myocardial infarction. A hazard ratio of 73 to 0.96 results in a 95% confidence interval;
110. The method results in a Kaplan-Meier rate of approximately 5.6% at the composite endpoint of 3 year coronary heart disease death or myocardial infarction;
111. The method results in a Kaplan-Meier rate of 5.6% at the composite endpoint of 3 year coronary heart disease death or myocardial infarction;
112. The method reduced the Kaplan-Meier rate of combined endpoints of coronary heart disease mortality or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. % Decrease;
113. The method approximates a Kaplan-Meier rate of compound endpoints for coronary heart disease mortality or stroke at year 3 compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Reduce by 1%;
114. The method numerically reduces the composite endpoint rate of cardiovascular mortality or myocardial infarction compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
115. The method numerically reduces the absolute risk of combined endpoints of cardiovascular death or myocardial infarction compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
116. The method poses a relative risk of less than 1 for the composite endpoint of cardiovascular mortality or myocardial infarction compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
117. The method numerically reduces the Kaplan-Meier rate of the combined endpoint of cardiovascular mortality or myocardial infarction compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
118. Hazard less than 1 in the time to the first composite endpoint of cardiovascular death or myocardial infarction when the method is compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Yields a ratio;
119. The method results in a numerical reduction in the percentage of patients with a composite endpoint of cardiovascular mortality or myocardial infarction events compared to a regimen in which daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to patients ;
120. Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method is approximately at the time to the first composite endpoint of cardiovascular death or myocardial infarction at 3 years Resulting in a hazard ratio of 0.85;
121. When the method is compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to the patient, the time to the first combined endpoint of cardiovascular death or myocardial infarction at year 3 is 0. Results in a hazard ratio of .85;
122. When the method is compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to the patient, the time to the first combined endpoint of cardiovascular death or myocardial infarction at year 3 is 0. Resulting in a hazard ratio of 74-0.96;
123. Compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient, the method is 0. 0 of time to the first composite endpoint of cardiovascular death or myocardial infarction at 3 years. A hazard ratio of 74 to 0.96 results in a 95% confidence interval;
124. The method results in a Kaplan-Meier rate of approximately 6.8% at the combined endpoint of cardiovascular death or myocardial infarction at year 3;
125. The method results in a Kaplan-Meier rate of 6.8% at the combined endpoint of cardiovascular death or myocardial infarction at year 3;
126. The method approximates the Kaplan-Meier rate of combined endpoints of cardiovascular death or stroke at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Reduce by 0%;
127. The method yields a Kaplan-Meier rate of 1.0 for combined endpoints of cardiovascular death or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. % Decrease;
128. The method numerically reduces mortality from any cause compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to a patient;
129. The method numerically reduces the Kaplan-Meier rate of death from any cause compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
130. The method results in a hazard ratio of less than 1 in the time to death from any first cause compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
131. The method provides a relative risk of less than 1 in the time to death from any first cause compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
132. The method results in a numerical reduction in the percentage of patients with death events of any cause compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
133. The method has a hazard ratio of approximately 0.89 in the time to death of any first cause in year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about;
134. The method results in a hazard ratio of 0.89 in the time to death from any first cause in the third year compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient ;
135. Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, the method has a 0.76 to 1.04 time to death from any first cause in the third year. Resulting in a hazard ratio;
136. Compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient, the method is 0.76 to 1.04 of time to first death from any cause in year 3 Provides a 95% confidence interval for the hazard ratio;
137. The method results in a Kaplan-Meier rate of approximately 4.7% for death from any cause in the third year;
138. The method results in a Kaplan-Meier rate of 4.7% for deaths from any cause in the third year;
139. The method reduces Kaplan-Meier rates of death from any cause in year 3 by approximately 0.5% compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
The method reduces the Kaplan-Meier rate of death from any cause in year 3 by 0.5% compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
140. The method numerically reduces the rate of emergency coronary reconstruction for unstable angina from any cause compared to a regimen in which daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to patients Let;
141. The method numerically reduces the Kaplan-Meier rate of emergency coronary reconstruction for unstable angina compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to a patient ;
142. The method is less than 1 in time to emergency coronary artery reconstruction of the first for unstable angina compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Resulting in a hazard ratio;
143. The method is numerically compared to the percentage of patients with emergency coronary reconstruction for unstable angina events compared to a dosing schedule in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Bring about a decline;
144. Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, the method is in time to emergency coronary artery reconstruction for the first unstable angina at year 3 Yields a hazard ratio of approximately 0.82;
145. Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, the method is in time to emergency coronary artery reconstruction for the first unstable angina at year 3 Resulting in a hazard ratio of 0.82;
146. Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, the method is in time to emergency coronary artery reconstruction for the first unstable angina at year 3 Resulting in a hazard ratio of 0.58 to 1.14;
147. 1 of time to emergency coronary artery reconstruction for first unstable angina at year 3 compared to a dosing regimen where the patient is given a daily maintenance dose of 75 mg to 150 mg aspirin alone A hazard ratio of 14 results in a 95% confidence interval;
148. The method numerically reduces the rate of coronary stent thrombosis from any cause compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to a patient;
149. The method numerically reduces the Kaplan-Meier rate of coronary stent thrombosis compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to a patient;
150. The method results in a hazard ratio of less than 1 in the time to first coronary stent thrombosis compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
151. The method results in a numerical reduction in the percentage of patients with coronary stent thrombosis events compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
152. Hazard ratio of approximately 0.82 for the time to first coronary stent thrombosis in year 3 compared to a regimen where the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to the patient Bring about;
153. The method has a hazard ratio of 0.82 at the time to first coronary stent thrombosis in year 3 compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Bring about;
154. Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method is 0.54 to 1.23 at the time to the first coronary stent thrombosis in year 3. Resulting in a hazard ratio of
155. Compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient, the method is 0.54 to 1.23 of time to first coronary stent thrombosis in year 3 Provides a 95% confidence interval for the hazard ratio;
156. The method poses a relative risk of less than 1 for coronary stent thrombosis compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
157. The method provides a relative risk reduction of approximately 18% for coronary stent thrombosis at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
158. The method results in a 18% relative risk reduction for coronary stent thrombosis in the third year compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
159. The first composite endpoint of cardiovascular mortality, myocardial infarction, or stroke as shown in FIGS. 4-7, as compared to a regimen in which the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to the patient In the subgroups shown in FIGS. 4-7, with the exception of subgroups with a time to hazard ratio of greater than 1, compared to a dosing schedule in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Numerically reduce the composite endpoint rate of cardiovascular death, myocardial infarction, or stroke;
160. Compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient so that the method has an average hazard ratio of less than 1 in the subgroups shown in FIGS. Results in a hazard ratio of less than 1 in the time to vascular death, myocardial infarction, or stroke first composite endpoint;
161. Compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient so that the method has an average hazard ratio of less than 1 in the subgroups shown in FIGS. Causes a numerical decrease in the percentage of patients with a composite endpoint of vascular death, myocardial infarction, or stroke event;
162. The method is the first of cardiovascular death, myocardial infarction, or stroke compared to a dosing regimen in which the daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient in the subgroup shown in FIGS. Results in the hazard ratios shown in FIGS. 4-7 at the time to
163. Cardiovascular mortality, as shown in FIGS. 4-7, compared to a regimen in which the method is a subgroup shown in FIGS. 4-7 and a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Provide a 95% confidence interval for the hazard ratio of time to the first composite endpoint of myocardial infarction or stroke;
164. The method results in an absolute risk reduction of approximately 2.15% at the combined endpoint of cardiovascular death, myocardial infarction, and stroke at 3 years, with patients over 75 years old;
165. The method results in a 2.15% absolute risk reduction at the combined endpoint of cardiovascular death, myocardial infarction, and stroke at 3 years, with patients over 75 years old;
166. The method results in an absolute risk reduction of approximately 1.38% at the combined endpoint of cardiovascular death, myocardial infarction, and stroke at 3 years, and the patient is under 65 years of age;
167. The method resulted in an absolute risk reduction of 1.38% at the composite endpoint of cardiovascular death, myocardial infarction, and stroke at 3 years, and the patient is under 65 years of age;
168. The method numerically reduces the composite endpoint rate of cardiovascular death, myocardial infarction, stroke, or TIMI hemorrhage compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Let;
169. The method quantifies the absolute risk of a composite endpoint of cardiovascular death, myocardial infarction, stroke, or TIMI hemorrhage compared to a regimen in which a patient is administered a daily maintenance dose of only 75 mg to 150 mg of aspirin Reduced to
170. The method quantifies the relative risk of a composite endpoint of cardiovascular death, myocardial infarction, stroke, or TIMI major bleeding compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone Reduced to
171. Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to a patient, the method is in time to the first composite endpoint of cardiovascular death, myocardial infarction, stroke or TIMI major bleeding, Resulting in a hazard ratio of less than 1;
172. The percentage of patients with a composite endpoint of cardiovascular death, myocardial infarction, stroke or TIMI major bleeding event compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient , Resulting in a numerical decline;
173. Until the first combined endpoint of cardiovascular death, myocardial infarction, stroke or TIMI hemorrhage at 3 years compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to patients Result in a hazard ratio of approximately 0.95;
174. Until the first combined endpoint of cardiovascular death, myocardial infarction, stroke or TIMI hemorrhage at 3 years compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to patients Resulting in a hazard ratio of 0.95 at the time of
175. Until the first combined endpoint of cardiovascular death, myocardial infarction, stroke or TIMI hemorrhage at 3 years compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to patients Resulting in a hazard ratio of 0.85 to 1.06;
176. Until the first combined endpoint of cardiovascular death, myocardial infarction, stroke or TIMI hemorrhage at 3 years compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to patients Yields a 95% confidence interval for a hazard ratio of 0.85 to 1.05 hours of time;
177. Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method is at the composite endpoint of 3 year cardiovascular death, myocardial infarction, stroke, or TIMI major bleeding, Results in a relative risk reduction of approximately 5%;
178. Compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, 5% of the combined endpoint of 3 years cardiovascular death, myocardial infarction, stroke or TIMI major bleeding Results in lower relative risk;
179. The method measures the composite endpoint rate of cardiovascular mortality, myocardial infarction, stroke, intracranial or lethal hemorrhage compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient To reduce;
180. The absolute risk of combined endpoints of cardiovascular mortality, myocardial infarction, stroke, intracranial or lethal bleeding compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg of aspirin alone Reduce numerically;
181. Compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method is at the combined endpoint of cardiovascular death, myocardial infarction, stroke, intracranial bleeding, or lethal bleeding, Results in a relative risk of less than 1;
182. The first composite endpoint of cardiovascular death, myocardial infarction, stroke, intracranial hemorrhage, or lethal hemorrhage compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg aspirin alone Result in a hazard ratio of less than 1;
183. The method has a combined endpoint of cardiovascular death, myocardial infarction, stroke, intracranial hemorrhage, or lethal bleeding event compared to a dosing regimen in which a patient is administered a daily maintenance dose of only 75 mg to 150 mg aspirin. Cause a numerical decline in the percentage of patients;
184. The first composite endpoint of cardiovascular death, myocardial infarction, stroke, intracranial hemorrhage, or lethal hemorrhage compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg aspirin alone Result in a hazard ratio of less than 1;
185. First method of cardiovascular death, myocardial infarction, stroke, intracranial hemorrhage, or lethal hemorrhage at 3 years compared to a regimen in which the patient is administered a daily maintenance dose of 75 mg to 150 mg aspirin alone Results in a hazard ratio of approximately 0.86 to the time to the composite endpoint of
186. First method of cardiovascular death, myocardial infarction, stroke, intracranial hemorrhage, or lethal hemorrhage at 3 years compared to a regimen in which the patient is administered a daily maintenance dose of 75 mg to 150 mg aspirin alone Results in a hazard ratio of 0.86 at the time to the composite endpoint of
187. First method of cardiovascular death, myocardial infarction, stroke, intracranial hemorrhage, or lethal hemorrhage at 3 years compared to a regimen in which the patient is administered a daily maintenance dose of 75 mg to 150 mg aspirin alone Resulting in a hazard ratio of 0.77 to 0.97 at the time to a composite endpoint of
188. First method of cardiovascular death, myocardial infarction, stroke, intracranial hemorrhage, or lethal hemorrhage at 3 years compared to a regimen in which the patient is administered a daily maintenance dose of 75 mg to 150 mg aspirin alone Yields a 95% confidence interval for a hazard ratio of 0.97 from 0.77 to the time to composite endpoint;
189. The method is a combination of cardiovascular death, myocardial infarction, stroke, intracranial hemorrhage, or lethal hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Results in a relative risk reduction of approximately 14% at the endpoint;
190. The method is a combination of cardiovascular death, myocardial infarction, stroke, intracranial hemorrhage, or lethal hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Results in a 14% relative risk reduction at the endpoint;
191. The method has a combined endpoint of annual cardiovascular death, myocardial infarction, or stroke of approximately 1.27% compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to the patient. Brings absolute risk reduction;
192. The method is 1.27% absolute at the combined endpoint of annual cardiovascular death, myocardial infarction, or stroke compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Results in reduced risk;
193. The method results in an approximate 0.53% reduction in absolute risk of 3-year cardiovascular mortality compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
194. The method results in a 0.53% absolute risk reduction in 3-year cardiovascular mortality compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
195. The method results in an approximate 0.72% reduction in absolute risk for myocardial infarction at year 3 compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
196. The method results in a 0.72% reduction in absolute risk for myocardial infarction at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
197. The method results in an absolute risk reduction of approximately 0.47% for myocardial infarction at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
198. The method results in a 0.47% reduction in absolute risk for 3-year relative myocardial infarction compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
199. The method results in approximately 79 cardiovascular mortality, myocardial infarction, or stroke treatment required number of composite endpoints compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
200. The method results in a combined endpoint of 79 cardiovascular mortality, myocardial infarction, or stroke treatment requirements compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
201. The method results in a required number of cardiovascular mortality treatments of approximately 189 compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
202. The method results in a required number of 189 cardiovascular mortality treatments compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
203. The method results in a required number of myocardial infarction treatments of approximately 139 compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg aspirin is administered to the patient;
204. The method results in a required number of 139 myocardial infarction treatments compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
205. The method results in a stroke treatment requirement of approximately 213 compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
206. The method results in a required number of stroke treatments of 213 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
207. The method is less than one hour to the first composite endpoint of cardiovascular death, myocardial infarction, or stroke event compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Within 30 days prior to administration, the patient must have a previous P2Y ₁₂ Discontinued inhibitor therapy;
208. Methods up to the first composite endpoint of a 3-year cardiovascular death, myocardial infarction, or stroke event as compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone In time, a hazard ratio of approximately 0.75 is achieved, and within 30 days prior to dosing, the patient will have a previous P2Y ₁₂ Discontinued inhibitor therapy;
209. Methods up to the first composite endpoint of a 3-year cardiovascular death, myocardial infarction, or stroke event as compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone In time, a hazard ratio of 0.75 is achieved, and the patient is treated within the previous P2Y within 30 days prior to administration. ₁₂ Discontinued inhibitor therapy;
210. Methods up to the first composite endpoint of a 3-year cardiovascular death, myocardial infarction, or stroke event as compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone Over time resulting in a hazard ratio of 0.61 to 0.92, and within 30 days prior to administration, the patient may have a previous P2Y ₁₂ Discontinued inhibitor therapy;
211. Methods up to the first composite endpoint of a 3-year cardiovascular death, myocardial infarction, or stroke event as compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone A hazard ratio of 0.61 to 0.92 of time results in a 95% confidence interval, and the patient can have a previous P2Y within 30 days prior to administration. ₁₂ Discontinued inhibitor therapy;
212. Methods up to the first composite endpoint of a 3-year cardiovascular death, myocardial infarction, or stroke event as compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone In time, a hazard ratio of less than 1 is achieved, and the patient is in the previous P2Y period from 30 days to 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
213. Methods up to the first composite endpoint of a 3-year cardiovascular death, myocardial infarction, or stroke event as compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone Over time resulting in a hazard ratio of approximately 0.82 and the patient was in the previous P2Y period from 30 days to 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
214. Methods up to the first composite endpoint of a 3-year cardiovascular death, myocardial infarction, or stroke event as compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone In time, a hazard ratio of 0.82 was achieved, and patients were treated with their previous P2Y from 30 days to 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
215. Methods up to the first composite endpoint of a 3-year cardiovascular death, myocardial infarction, or stroke event as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient In time, a hazard ratio of 0.65 to 1.02 was achieved, and patients were treated with their previous P2Y from 31 days to 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
216. Methods up to the first composite endpoint of a 3-year cardiovascular death, myocardial infarction, or stroke event as compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone A hazard ratio of 0.65 to 1.02 of time results in a 95% confidence interval, and patients are given prior P2Y from 31 days to 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
217. 27% of the combined endpoints of cardiovascular mortality, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Resulting in a relative risk reduction, patients within 30 days prior to administration ₁₂ Discontinued inhibitor therapy;
218. The method is approximately 27% at the combined endpoint of cardiovascular mortality, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Within 30 days prior to administration, the patient is ₁₂ Discontinued inhibitor therapy;
219. The method approximates the combined endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a 2% reduction in absolute risk, and the patient has not received prior P2Y within 30 days prior to administration. ₁₂ Discontinued inhibitor therapy;
220. The method is 2.2% for the combined endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Within 30 days prior to administration, the patient must have a previous P2Y ₁₂ Discontinued inhibitor therapy;
221. The method is approximately 14% at the combined endpoint of cardiovascular mortality, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. The relative risk is reduced, and patients are treated with the previous P2Y from 31 days to 1 year prior to administration ₁₂ Discontinued inhibitor therapy;
222. 14% of the combined endpoints of cardiovascular mortality, myocardial infarction, or stroke at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Resulting in a relative risk reduction, and patients may have received previous P2Y from 31 days to 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
223. The method approximates the combined endpoint of cardiovascular mortality, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a 1% reduction in absolute risk, patients were treated with the previous P2Y from 31 days to 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
224. The method is 1.1% for the combined endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient The absolute risk of the patient is reduced, and the patient has a previous P2Y between 31 days and 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
225. The method numerically reduces the composite endpoint rate of cardiovascular death, myocardial infarction, or stroke, as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, Within 30 days prior to administration, the previous P2Y ₁₂ Discontinued inhibitor therapy;
226. The method numerically reduces the absolute risk of a composite endpoint of cardiovascular mortality, myocardial infarction, or stroke as compared to a dosing regimen where a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient Within 30 days prior to administration ₁₂ Discontinued inhibitor therapy;
227. The method poses a relative risk of less than 1 for a composite endpoint of cardiovascular mortality, myocardial infarction, or stroke compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient Within 30 days prior to administration ₁₂ Discontinued inhibitor therapy;
228. The method numerically measures the Kaplan-Meier rate of combined endpoints of cardiovascular mortality, myocardial infarction, or stroke compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone Within 30 days prior to administration ₁₂ Discontinued inhibitor therapy;
229. The method resulted in a Kaplan-Meier rate of approximately 8.0% at the composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years, and the patient received previous P2Y within 30 days prior to administration. ₁₂ Discontinued inhibitor therapy;
230. The method resulted in a Kaplan-Meier rate of 8.0% at the composite endpoint of cardiovascular mortality, myocardial infarction, or stroke at 3 years, and within 30 days prior to administration, the patient ₁₂ Discontinued inhibitor therapy;
231. The method is less than 1 in time to cardiovascular death, myocardial infarction, or stroke first composite endpoint compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Hazard ratio is achieved, and the patient will have received the previous P2Y within 30 days prior to administration. ₁₂ Discontinued inhibitor therapy;
232. The method measures the percentage of patients with a composite endpoint of cardiovascular death, myocardial infarction, or stroke event as compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Within 30 days prior to administration, the patient must have a previous P2Y ₁₂ Discontinued inhibitor therapy;
233. The method is based on Kaplan-Meier rates of compound endpoints of cardiovascular mortality, myocardial infarction, or stroke at 3 years compared to a regimen in which patients are administered daily maintenance doses of 75 mg to 150 mg aspirin alone. Within approximately 30 days prior to administration, the patient has ₁₂ Discontinued inhibitor therapy;
234. Kaplan-Meier rate of compound endpoints of cardiovascular mortality, myocardial infarction, or stroke at 3 years compared to a regimen in which the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to patients 1.9%, and within 30 days prior to administration, the patient must have a previous P2Y ₁₂ Discontinued inhibitor therapy;
235. The method numerically reduces the composite endpoint rate of cardiovascular death, myocardial infarction, or stroke, as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, In the previous 31 days to 1 year prior to administration ₁₂ Discontinued inhibitor therapy;
236. The method numerically reduces the absolute risk of a composite endpoint of cardiovascular mortality, myocardial infarction, or stroke as compared to a dosing regimen where a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient , Patients will receive previous P2Y from 31 days to 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
237. The method poses a relative risk of less than 1 for a composite endpoint of cardiovascular mortality, myocardial infarction, or stroke compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient , Patients will receive previous P2Y from 31 days to 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
238. The method numerically measures the Kaplan-Meier rate of combined endpoints of cardiovascular mortality, myocardial infarction, or stroke compared to a regimen in which a patient is administered a daily maintenance dose of 75 mg to 150 mg of aspirin alone The patient will have a previous P2Y between 31 days and 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
239. The method resulted in a Kaplan-Meier rate of approximately 8.1% for the combined endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years, and patients were previously treated between 31 days and 1 year prior to administration. P2Y ₁₂ Discontinued inhibitor therapy;
240. The method resulted in a Kaplan-Meier rate of 8.1% at the combined endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years, and patients were previously treated between 31 days and 1 year prior to administration. P2Y ₁₂ Discontinued inhibitor therapy;
241. The method is less than 1 in time to cardiovascular death, myocardial infarction, or stroke first composite endpoint compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Resulting in a hazard ratio, and the patient may have a previous P2Y between 31 days and 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
242. The method measures the percentage of patients with a composite endpoint of cardiovascular death, myocardial infarction, or stroke event as compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. The patient has a previous P2Y between 31 days and 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
243. Kaplan-Meier rate of compound endpoints of cardiovascular mortality, myocardial infarction, or stroke at 3 years compared to a regimen in which the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to patients Decreased by approximately 0.6%, and the patient had a previous P2Y between 31 days and 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
244. Kaplan-Meier rate of compound endpoints of cardiovascular mortality, myocardial infarction, or stroke at 3 years compared to a regimen in which the method is administered daily maintenance doses of 75 mg to 150 mg aspirin alone to patients Decreased by 0.6% and patients were treated with the previous P2Y from 31 days to 1 year prior to administration. ₁₂ Discontinued inhibitor therapy;
245. The method results in a numerical reduction in total mortality compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
246. In a patient, the method comprises administering a twice daily pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier, and a daily maintenance dose of 75-100 mg of aspirin to the patient. Effective in reducing the composite endpoint rate of cardiovascular death, myocardial infarction, or stroke;
247. Compared to the method wherein the twice daily pharmaceutical composition comprising 90 mg ticagrelor and a pharmaceutically acceptable carrier, and a daily maintenance dose of 75-100 mg aspirin is administered to the patient Reduce the rate of irreversible harm to patients;
248. Compared to the method wherein the twice daily pharmaceutical composition comprising 90 mg ticagrelor and a pharmaceutically acceptable carrier, and a daily maintenance dose of 75-100 mg aspirin is administered to the patient Reduce the composite endpoint rate of cardiovascular death, myocardial infarction, stroke, intracranial bleeding, or lethal bleeding;
249. Compared to the method wherein the twice daily pharmaceutical composition comprising 90 mg ticagrelor and a pharmaceutically acceptable carrier, and a daily maintenance dose of 75-100 mg aspirin is administered to the patient Numerically reduce the composite endpoint rate of cardiovascular death, myocardial infarction, stroke, intracranial bleeding, or lethal bleeding;
250. Compared to the method wherein the twice daily pharmaceutical composition comprising 90 mg ticagrelor and a pharmaceutically acceptable carrier, and a daily maintenance dose of 75-100 mg aspirin is administered to the patient Improve the risk-benefit profile; or
251. The method improves the risk-benefit profile of ticagrelor administered on an aspirin background.

In some embodiments, the method meets at least one of the following safety endpoints:
1. The method does not result in a hazard ratio of more than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
2. The method does not result in a hazard ratio that is nominally significantly greater than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
3. The method does not result in a hazard ratio greater than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
4). The method does not produce a hazard ratio that is nominally significantly greater than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
5). The method results in a numerical increase of less than 0.5 in the number of TIMI major bleeding events per 100 patient years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
6). The method results in a numerical increase of approximately 0.44 in the number of TIMI major bleeding events per 100 patient years compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
7). The method results in a numerical increase of 0.44 in the number of TIMI major bleeding events per 100 patient years compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
8). The method does not result in a numerical increase in the number of lethal bleeding events per 100 patient years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
9. The method results in a numerical increase of approximately 0.05 in the number of intracranial hemorrhage events per 100 patient years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
10. The method results in a numerical increase of 0.05 in the number of intracranial hemorrhage events per 100 patient years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
11. The method results in a difference in Kaplan-Meier rates of less than 0.05% in 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient ;
12 The method results in a Kaplan-Meier rate difference of less than 0.1% for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
13. The method results in a Kaplan-Meier rate of approximately 0.3% for the third year of lethal bleeding;
14 The method results in a Kaplan-Meier rate of 0.3% for the third year of lethal bleeding;
15. The method results in a numerical reduction in the rate of lethal bleeding events for TIMI major bleeding events compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg of aspirin alone are administered to the patient;
16. The method results in a numerical reduction in the rate of lethal bleeding events for TIMI major bleeding events compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg of aspirin alone are administered to the patient;
17. The method results in a reduction in the rate of lethal bleeding events for TIMI major bleeding events compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg of aspirin alone are administered to the patient;
18. The method results in a reduction in the rate of lethal bleeding events for TIMI major bleeding events compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg of aspirin alone are administered to the patient;
19. The method results in a numerical reduction of approximately 0.13 in the lethal bleeding event rate for TIMI major bleeding events compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
20. The method results in a numerical reduction of 0.13 in the lethal bleeding event rate for TIMI major bleeding events compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
21. The method results in a 3-year dyspnea event rate of approximately 15.8%;
22. The method results in a 3 year dyspnea event rate of 15.8%;
23. The method results in a numerical reduction in the intermediate duration of resolved adverse dyspnea events as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
24. The method results in a reduction in the intermediate duration of resolved dyspnea adverse events compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
25. The method results in a numerical reduction of approximately 18 days in the intermediate duration of resolved dyspnoea adverse events compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient ;
26. The method results in a numerical decrease of 18 days in the intermediate duration of resolved dyspnea adverse events compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
27. The method results in a numerical reduction in the intermediate duration of resolved adverse dyspnea events as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
28. The method does not result in reduced lung function after 1 month;
29. The method does not result in reduced lung function after at least 6 months;
30. The method does not result in a hazard ratio of more than 1 for a 3 year renal adverse event compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
31. The method does not produce a hazard ratio that is nominally significantly greater than 1 for 3 year renal adverse events compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
32. The method does not result in a hazard ratio of more than 1 for 3 year gout adverse events compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
33. The method does not result in a hazard ratio that is nominally significantly greater than 1 for 3 year gout adverse events compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
34. The method does not result in a hazard ratio of more than 1 for a 3-year bradyarrhythmia adverse event compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
35. The method results in a hazard ratio that is nominally significantly greater than 1 for a 3-year bradyarrhythmia adverse event compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to a patient. Absent;
36. The method causes syncope in approximately 0.9% of patients;
37. The method causes syncope in 0.9% of patients;
38. The method results in a reversible increase in serum uric acid levels;
39. The method results in an increase of approximately 0.2 mg / dL in serum uric acid levels compared to serum uric acid levels prior to administration;
40. The method provides a numerical increase of approximately 142% in relative risk of major bleeding at TIMI compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg of aspirin alone are administered to patients based on a final dose exposure response model Bring about;
41. The method shows a 142% numerical increase in TIMI major bleeding relative risk compared to a dosing regimen where daily maintenance doses of 75 mg to 150 mg aspirin alone are administered to patients based on a final dose exposure response model. Bring about;
42. The method resulted in an absolute risk increase of approximately 2.38% in the third year of TIMI hemorrhage compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin was administered to the patient, and the patient was 75 years old Exceeding
43. The method resulted in an absolute risk increase of approximately 1.05% in the third year of TIMI hemorrhage compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin is administered to the patient, and the patient is 65 years old Less than;
44. The method results in an approximate 1.24% increase in absolute risk for major TIMI bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
45. The method results in a 1.24% increase in absolute risk for major TIMI bleeding compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
46. The method results in an absolute risk increase of approximately 0.14% for intracranial hemorrhage compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
47. The method results in an absolute risk increase of approximately 0.14% for intracranial hemorrhage compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
48. The method results in an absolute risk reduction of approximately 0.01% for lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
49. The method results in an absolute risk reduction of approximately 0.01% for lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
50. The method results in approximately 81 TIMI major bleeding hazard numbers compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
51. The method results in a necessary TIMI bleeding haemorrhage number of 81 compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
52. The method results in a necessary number of intracranial bleeding hazards of approximately 714 compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient; or 53. The method results in a required number of intracranial hemorrhage damage of 714 compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;

  In some embodiments, the disclosed method results in one of the efficacy endpoints listed above. In some further embodiments, the disclosed methods provide at least one of the efficacy endpoints listed above. In some further embodiments, the disclosed methods provide at least two of the efficacy endpoints listed above. In still some further embodiments, the disclosed methods result in 2, 3 or 4 efficacy endpoints listed above. In some further embodiments, the disclosed methods result in 5 to 251 efficacy endpoints listed above.

  In some embodiments, the disclosed method provides one of the safety endpoints listed above. In some further embodiments, the disclosed methods provide at least one of the safety endpoints listed above. In some further embodiments, the disclosed methods provide at least two of the safety endpoints listed above. In still some further embodiments, the disclosed methods result in 2, 3 or 4 safety endpoints listed above. In some further embodiments, the disclosed methods result in 5 to 53 safety endpoints listed above.

  In some embodiments, the disclosed method results in one of the efficacy endpoints listed above and one of the safety endpoints listed above. In some further embodiments, the disclosed methods result in at least one of the efficacy endpoints listed above and at least one of the safety endpoints listed above. In still some further embodiments, the disclosed method comprises the 2, 3, 4, 5, or 6 efficacy endpoints listed above and the 2, 3, 4, 5, Or 6 safety endpoints. In some further embodiments, the disclosed methods result in 1 to 251 efficacy endpoints listed above and 1 to 53 safety endpoints listed above.

For example, in some embodiments, the method meets at least one of the following combined safety and efficacy conditions:
(A) the absolute absolute of composite endpoints of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which the patient is given a daily maintenance dose of 75 mg to 150 mg of aspirin alone The risk is numerically reduced and the method has a hazard ratio greater than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not bring;
(B) The method is less than 1 relative to the combined endpoint of cardiovascular death, myocardial infarction, or stroke, compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Poses a risk and the method does not result in a hazard ratio of more than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
(C) The method reduces the Kaplan-Meier rate for combined endpoints of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Numerically reduced, the method does not result in a hazard ratio of more than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient ;
(D) The method is statistically associated with a composite endpoint rate of cardiovascular death, myocardial infarction, or stroke compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. The method resulted in a hazard ratio of more than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone was administered to the patient. Absent;
(E) the method is statistically associated with a combined endpoint of cardiovascular death, myocardial infarction, or stroke, as compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Significantly resulting in a relative risk of less than 1, the method has more than 1 hazard in lethal bleeding at 3 years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient Does not yield a ratio;
(F) Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method is at a composite endpoint of 3 year cardiovascular death, myocardial infarction, or stroke, Results in a Kaplan-Meier rate of approximately 7.8%, and the method does not result in a hazard ratio of more than 1 in the third year of lethal bleeding;
(G) when the method is in time to the first composite endpoint of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient; Resulting in a hazard ratio of less than 1, and the method has a hazard ratio of greater than 1 for 3 years of lethal hemorrhage compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not bring
(H) Percentage of patients with a combined endpoint event of cardiovascular death, myocardial infarction, or stroke as compared to a regimen where the method is administered daily maintenance doses of 75 mg to 150 mg of aspirin alone to the patient. Resulting in a numerical decline, and the method has a hazard ratio greater than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not bring;
(I) When the method is in time to the first composite endpoint of cardiovascular death, myocardial infarction, or stroke compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Resulting in a hazard ratio that is statistically significantly less than 1, and the method is associated with a 3rd year lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not result in a hazard ratio greater than 1;
(J) The first composite endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg of aspirin alone The method results in a hazard ratio of approximately 0.84; the method results in a 3 year lethal bleeding compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Does not result in a hazard ratio greater than 1;
(K) The first composite endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg aspirin alone Leading to a hazard ratio of 0.74 to 0.95, and the method is lethal at 3 years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not cause hazard ratios greater than 1 for sexual bleeding;
(L) The first combined end of a 3-year cardiovascular death, myocardial infarction, or stroke event compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg of aspirin alone A hazard ratio of 0.74 to 0.95 of time to point provides a 95% confidence interval and the method is compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. 3 years of lethal bleeding does not result in a hazard ratio greater than 1;
(M) the absolute absolute of the combined endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient The risk is reduced by approximately 1.27%, and the method has more than 1 hazard in 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not yield a ratio;
(N) Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method has a composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years, More than 1 hazard in fatal bleeding at 3 years compared to a regimen that resulted in a relative risk reduction of approximately 17% and a daily maintenance dose of 75 mg to 150 mg aspirin alone was administered to the patient. Does not yield a ratio;
(O) Kaplan, a composite endpoint of 3-year cardiovascular death, myocardial infarction, or stroke, as compared to a dosing regimen in which the patient is given a daily maintenance dose of 75 mg to 150 mg of aspirin alone Reduced Meyer's rate by approximately 1.2%, and the method increased 1 to 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin was administered to the patient. Or (p) that the method is compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient at year 3 cardiovascular death, myocardial infarction, Or reduce the percentage of patients with a composite endpoint event of stroke by approximately 1.3%, and the method allows patients to receive a daily maintenance dose of 75 mg to 150 mg aspirin alone Compared to given to the dosage regimen, a lethal hemorrhage third year, it does not lead to a hazard ratio of greater than 1.

In some other exemplary embodiments, the method meets at least one of the following combined safety and efficacy conditions:
(A) The method quantifies the absolute risk of a composite endpoint of cardiovascular mortality, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method has a hazard ratio that is nominally significantly greater than 1 for 3 years of lethal bleeding. Does not bring;
(B) The method is less than 1 relative to the combined endpoint of cardiovascular death, myocardial infarction, or stroke, compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. The risk poses that the method has a hazard ratio that is nominally significantly greater than 1 for lethal bleeding at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not bring;
(C) The method reduces the Kaplan-Meier rate for combined endpoints of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Numerically reduced and the method has a nominally significantly greater than 1 hazard at 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not yield a ratio;
(D) The method is statistically associated with a composite endpoint rate of cardiovascular death, myocardial infarction, or stroke compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. The method is nominally significantly more than 1 in 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Does not cause hazard ratios;
(E) the method is statistically associated with a combined endpoint of cardiovascular death, myocardial infarction, or stroke, as compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Significantly resulting in a relative risk of less than 1, the method is nominally significantly more significant at 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not result in a hazard ratio greater than 1;
(F) Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method is at a composite endpoint of 3 year cardiovascular death, myocardial infarction, or stroke, Results in a Kaplan-Meier rate of approximately 7.8%, and the method does not result in a hazard ratio that is nominally significantly greater than 1 for 3 years of lethal bleeding;
(G) when the method is in time to the first composite endpoint of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient; Resulting in a hazard ratio of less than 1, the method is nominally significantly more significant at 1 year of lethal bleeding at 3 years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not result in a hazard ratio greater than
(H) Percentage of patients with a combined endpoint event of cardiovascular death, myocardial infarction, or stroke as compared to a regimen where the method is administered daily maintenance doses of 75 mg to 150 mg of aspirin alone to the patient. The method is nominally significantly more than 1 in 3 years of lethal hemorrhage compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient Does not cause hazard ratios;
(I) When the method is in time to the first composite endpoint of cardiovascular death, myocardial infarction, or stroke compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Resulting in a hazard ratio that is statistically significantly less than 1, and the method is associated with a 3rd year lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not result in a hazard ratio that is nominally significantly greater than 1;
(J) The first composite endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg of aspirin alone To a hazard ratio of approximately 0.84, and the method results in a 3rd year lethal bleeding compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not result in a hazard ratio that is nominally significantly greater than 1;
(K) The first composite endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg aspirin alone Leading to a hazard ratio of 0.74 to 0.95, and the method is lethal at 3 years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not result in a hazard ratio that is nominally significantly greater than 1;
(L) The first combined end of a 3-year cardiovascular death, myocardial infarction, or stroke event compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg of aspirin alone A hazard ratio of 0.74 to 0.95 of time to point provides a 95% confidence interval and the method is compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. 3 years of lethal bleeding does not result in a hazard ratio that is nominally significantly greater than 1;
(M) the absolute absolute of the combined endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient The risk is reduced by approximately 1.27%; the method is nominally significant for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not result in a hazard ratio greater than 1;
(N) Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method has a composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years, Resulting in a relative risk reduction of approximately 17%, and the method is nominally significantly more significant at 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not result in a hazard ratio greater than 1;
(O) Kaplan, a composite endpoint of 3-year cardiovascular death, myocardial infarction, or stroke, as compared to a dosing regimen in which the patient is given a daily maintenance dose of 75 mg to 150 mg of aspirin alone Reduced Meyer's rate by approximately 1.2% and the method is nominally associated with lethal bleeding at 3 years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. No significant hazard ratio greater than 1; or (p) cardiovascular mortality at 3 years compared to a regimen where the daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Reduces the percentage of patients with combined endpoint events of cerebral, myocardial infarction, or stroke by approximately 1.3% and the method maintains daily maintenance of 75 mg to 150 mg aspirin only Compared to regimens amount is administered to a patient, the lethal bleeding third year, does not lead to a hazard ratio of greater than nominally significant 1;

In some further exemplary embodiments, the method meets at least one of the following combined safety and efficacy conditions:
(A) The method quantifies the absolute risk of a composite endpoint of cardiovascular mortality, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient The method does not result in a hazard ratio of more than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
(B) The method is less than 1 relative to the combined endpoint of cardiovascular death, myocardial infarction, or stroke, compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Presents a risk and the method does not result in a hazard ratio greater than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
(C) The method reduces the Kaplan-Meier rate for combined endpoints of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Numerically reduced and the method does not result in a hazard ratio greater than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
(D) The method is statistically associated with a composite endpoint rate of cardiovascular death, myocardial infarction, or stroke compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. The method does not result in a hazard ratio greater than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient ;
(E) the method is statistically associated with a combined endpoint of cardiovascular death, myocardial infarction, or stroke, as compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Significantly resulting in a relative risk of less than 1, the method has more than 1 hazard in lethal bleeding at 3 years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient Does not yield a ratio;
(F) Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method is at a composite endpoint of 3 year cardiovascular death, myocardial infarction, or stroke, Results in a Kaplan-Meier rate of approximately 7.8%, and the method does not result in a hazard ratio of more than 1 in the third year of intracranial hemorrhage;
(G) when the method is in time to the first composite endpoint of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient; Resulting in a hazard ratio of less than 1, and the method has a hazard ratio of greater than 1 for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not bring;
(H) Percentage of patients with a combined endpoint event of cardiovascular death, myocardial infarction, or stroke as compared to a regimen where the method is administered daily maintenance doses of 75 mg to 150 mg of aspirin alone to the patient. The method does not provide a hazard ratio greater than 1 for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient ;
(I) When the method is in time to the first composite endpoint of cardiovascular death, myocardial infarction, or stroke compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Resulting in a hazard ratio that is statistically significantly less than 1, and the method results in intracranial hemorrhage at 3 years compared to a dosing schedule in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient, Does not result in a hazard ratio greater than 1;
(J) The first composite endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg of aspirin alone Resulting in a hazard ratio of approximately 0.84, and the method results in a 3 year intracranial hemorrhage compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient, Does not result in a hazard ratio greater than 1;
(K) The first composite endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg aspirin alone To a hazard ratio of 0.74 to 0.95, and the method of the third year of the skull compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not cause a hazard ratio greater than 1 for internal bleeding;
(L) The first combined end of a 3-year cardiovascular death, myocardial infarction, or stroke event compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg of aspirin alone A hazard ratio of 0.74 to 0.95 of time to point provides a 95% confidence interval and the method is compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not cause a hazard ratio greater than 1 for intracranial bleeding at year 3;
(M) the absolute absolute of the combined endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Reduces risk by approximately 1.27%; the method has a hazard ratio greater than 1 for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Does not bring
(N) Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method has a composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years, Hazard ratio greater than 1 for intracranial hemorrhage at 3 years compared to a dosing regimen in which a daily maintenance dose of only 75 mg to 150 mg aspirin is administered to the patient, resulting in a relative risk reduction of approximately 17% Does not bring
(O) Kaplan, a composite endpoint of 3-year cardiovascular death, myocardial infarction, or stroke, as compared to a dosing regimen in which the patient is given a daily maintenance dose of 75 mg to 150 mg of aspirin alone Reduce Meyer's rate by approximately 1.2% and the method exceeds 1 in 3 years of intracranial hemorrhage compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient Does not result in a hazard ratio; or (p) the method results in a 3-year cardiovascular death, myocardial infarction, or compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient The percentage of patients with a composite endpoint event of stroke is reduced by approximately 1.3%, and the method allows patients to receive a daily maintenance dose of only 75 mg to 150 mg of aspirin. Compared to given to the dosage regimen, the intracranial hemorrhage of 3 years, does not lead to a hazard ratio of greater than 1.

In some still further exemplary embodiments, the method meets at least one of the following combined safety and efficacy conditions:
(A) The method quantifies the absolute risk of a composite endpoint of cardiovascular mortality, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient The method resulted in a hazard ratio that was nominally significantly greater than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone was administered to the patient. Absent;
(B) The method is less than 1 relative to the combined endpoint of cardiovascular death, myocardial infarction, or stroke, compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Presents a risk and the method results in a hazard ratio that is nominally significantly greater than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Absent;
(C) The method reduces the Kaplan-Meier rate for combined endpoints of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Hazard ratio, which is numerically reduced and is significantly greater than 1 for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not bring
(D) The method is statistically associated with a composite endpoint rate of cardiovascular death, myocardial infarction, or stroke compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. The method is significantly more than 1 hazard for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient. Does not yield a ratio;
(E) the method is statistically associated with a combined endpoint of cardiovascular death, myocardial infarction, or stroke, as compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Significantly resulting in a relative risk of less than 1, the method is nominally significantly 1 for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not result in a hazard ratio greater than
(F) Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method is at a composite endpoint of 3 year cardiovascular death, myocardial infarction, or stroke, Resulting in a Kaplan-Meier rate of approximately 7.8% and the method does not result in a hazard ratio that is nominally significantly greater than 1 for intracranial hemorrhage at 3 years;
(G) when the method is in time to the first composite endpoint of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient; Resulting in a hazard ratio of less than 1, the method nominally significantly increases 1 for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not lead to a greater hazard ratio;
(H) Percentage of patients with a combined endpoint event of cardiovascular death, myocardial infarction, or stroke as compared to a regimen where the method is administered daily maintenance doses of 75 mg to 150 mg of aspirin alone to the patient. And a method that has a nominally significantly greater than 1 hazard for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not yield a ratio;
(I) When the method is in time to the first composite endpoint of cardiovascular death, myocardial infarction, or stroke compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Resulting in a hazard ratio that is statistically significantly less than 1, and the method results in intracranial hemorrhage at 3 years compared to a dosing schedule in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient, Does not produce a hazard ratio that is nominally significantly greater than 1;
(J) The first composite endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg of aspirin alone Resulting in a hazard ratio of approximately 0.84, and the method results in a 3 year intracranial hemorrhage compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient, Does not produce a hazard ratio that is nominally significantly greater than 1;
(K) The first composite endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg aspirin alone To a hazard ratio of 0.74 to 0.95, and the method of the third year of the skull compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Internal bleeding does not result in a hazard ratio that is nominally significantly greater than 1;
(L) The first combined end of a 3-year cardiovascular death, myocardial infarction, or stroke event compared to a regimen in which the method is administered to a patient with a daily maintenance dose of 75 mg to 150 mg of aspirin alone A hazard ratio of 0.74 to 0.95 of time to point provides a 95% confidence interval and the method is compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. 3 years of intracranial hemorrhage does not produce a hazard ratio that is nominally significantly greater than 1;
(M) the absolute absolute of the combined endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient The risk is reduced by approximately 1.27%; the method is nominally significantly 1 for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not result in a hazard ratio greater than
(N) Compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to a patient, the method has a composite endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years, This resulted in a relative risk reduction of approximately 17%, and the method was nominally significantly 1 for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone was administered to the patient. Does not result in a hazard ratio greater than
(O) Kaplan, a composite endpoint of 3-year cardiovascular death, myocardial infarction, or stroke, as compared to a dosing regimen in which the patient is given a daily maintenance dose of 75 mg to 150 mg of aspirin alone Reduced Meyer's rate by approximately 1.2% and the method is nominally significant for intracranial hemorrhage at 3 years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient Does not result in a hazard ratio of greater than 1; or (p) the cardiovascular mortality at year 3 compared to a regimen in which the daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, Reduced the percentage of patients with myocardial infarction or a combined endpoint event of stroke by approximately 1.3%, and the method maintains daily maintenance of 75 mg to 150 mg aspirin only Compared to regimens amount is administered to a patient, the intracranial hemorrhage of 3 years, does not lead to a hazard ratio of greater than nominally significant 1.

  In some embodiments, the method provides a combined endpoint rate of cardiovascular death, myocardial infarction, or stroke as compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a numerical decline, and the method has a hazard ratio of more than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Will not bring.

  In some embodiments, the method provides a combined endpoint rate of cardiovascular death, myocardial infarction, or stroke as compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a statistically significant reduction, and the method is more than 1 in 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Does not bring hazard ratio.

  In some embodiments, the method provides a combined endpoint rate of cardiovascular death, myocardial infarction, or stroke as compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a numerical decline, and the method has a hazard ratio of more than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Will not bring.

  In some embodiments, the method provides a combined endpoint rate of cardiovascular death, myocardial infarction, or stroke as compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a statistically significant reduction, and the method is more than 1 in 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Does not bring hazard ratio.

  In some embodiments, the method provides a combined endpoint rate of cardiovascular death, myocardial infarction, or stroke as compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a statistically significant reduction, and the method is nominally significant for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not result in a hazard ratio greater than 1.

  In some embodiments, the method provides a combined endpoint rate of cardiovascular death, myocardial infarction, or stroke as compared to a dosing regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a statistically significant reduction, and the method is nominally significant for intracranial hemorrhage at 3 years compared to a dosing regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Does not result in a hazard ratio greater than 1.

In some embodiments of all aspects, the pharmaceutical composition comprising ticagrelor and a pharmaceutically acceptable carrier is a mixture of mannitol and dicalcium phosphate present in an amount of 20% to 70% by weight, 3% Further comprising hydroxypropylcellulose present in an amount of -6% by weight, sodium starch glycolate present in an amount of 2% -6% by weight, and magnesium stearate present in an amount of 0.5% -1% by weight. Become.
That is, this specification includes the disclosure of the following invention.
[1] In a patient with recognized need, comprising administering to a patient a pharmaceutical composition comprising 60 mg of ticagrelor and a pharmaceutically acceptable carrier twice daily. A method of reducing the composite endpoint rate of death, myocardial infarction, or stroke;
The patient has a history of myocardial infarction;
A daily maintenance dose of 75 mg to 150 mg of aspirin is also administered to the patient;
The method wherein the composite endpoint rate in the patient is reduced compared to a dosing regimen wherein a daily maintenance dose of the 75 mg to 150 mg aspirin alone is administered to the patient.
[2] The method according to [1], wherein the daily maintenance dose of the aspirin is 75 mg to 100 mg.
[3] The patient has a history of myocardial infarction for at least 12 months prior to twice daily administration of the pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier. ] Or the method according to [2].
[4] The patient has a history of myocardial infarction between 12 and 36 months prior to twice daily administration of the pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier. The method according to any one of 1] to [3].
[5] The method according to any one of [1] to [4], wherein the patient has a history of myocardial infarction as a result of acute coronary syndrome.
[6] Prior to the administration, a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier is administered to the patient twice a day for a portion of 12 months after the acute coronary syndrome The method according to [5].
[7] Prior to the administration, a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier was administered to the patient twice a day for 12 months after the acute coronary syndrome. 5].
[8] Initial dose of 180 mg ticagrelor prior to twice daily administration of a pharmaceutical composition comprising 90 mg ticagrelor and a pharmaceutically acceptable carrier in a portion of the 12 months after the acute coronary syndrome The method according to [6] or [7], wherein a pharmaceutical composition comprising is administered to the patient.
[9] (a) The method of the combined endpoint of cardiovascular mortality, myocardial infarction, or stroke compared to a dosing regimen wherein a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Numerically reduce absolute risk;
(B) The method is less than 1 for the combined endpoint of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Cause a relative risk of;
(C) Kaplan Meier of the composite endpoint of cardiovascular death, myocardial infarction, or stroke as compared to a dosing regimen wherein a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Reduce the rate numerically;
(D) The method provides statistics on the composite endpoint rate of cardiovascular mortality, myocardial infarction, or stroke as compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a significant reduction in chemistry;
(E) The method provides statistics on the composite endpoint of cardiovascular death, myocardial infarction, or stroke as compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a relative risk significantly less than 1;
(F) the method results in a Kaplan-Meier rate of approximately 7.8% for the composite endpoint of cardiovascular death, myocardial infarction, or stroke at year 3;
(G) Time to first composite endpoint of cardiovascular death, myocardial infarction, or stroke, as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Results in a hazard ratio of less than 1;
(H) for patients with a composite endpoint event of cardiovascular death, myocardial infarction, or stroke, as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Cause a numerical drop in percentage;
(I) time to first composite endpoint of cardiovascular mortality, myocardial infarction, or stroke as compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient; Results in a hazard ratio that is statistically significantly less than 1,
(J) the first combined end of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Bring a hazard ratio of about 0.84 to the time to point,
(K) the first combined end of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Bring a hazard ratio of 0.74-0.95 to the time to point,
(I) the first combination of cardiovascular death, myocardial infarction, or stroke event at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient The hazard ratio of 0.74 to 0.95 of time to endpoint yields a 95% confidence interval,
(M) the combined endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 as compared to a regimen wherein a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Reduce the absolute risk of about 1.27%;
(N) the combined endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 as compared to a regimen wherein a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Results in a relative risk reduction of approximately 17%;
(O) the combined endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen wherein a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient; Reduce the Kaplan-Meier rate by approximately 1.2%;
(P) Compound endpoint event of cardiovascular mortality, myocardial infarction, or stroke at year 3 compared to a dosing regimen where the daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Reduce the percentage of patients with approximately 1.3%;
(Q) the method results in a numerical reduction in cardiovascular mortality compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient; or
(R) The method results in a numerical reduction in total mortality compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient
The method according to any one of [1] to [8], wherein at least one of the following conditions is satisfied.
[10] The (a) method resulted in a hazard ratio of more than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone was administered to the patient. Absent;
(B) The method has a hazard ratio that is nominally significantly greater than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not bring;
(C) The method does not result in a hazard ratio of more than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
(D) The method results in a hazard ratio that is nominally significantly greater than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Absent;
(E) the method does not pose a relative risk of more than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
(F) The method has a relative risk of nominally significantly greater than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not bring;
(G) the method does not pose a relative risk of more than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
(H) The method results in a relative risk that is nominally significantly greater than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Absent;
(I) The method shows a numerical value of less than 0.5 for the number of TIMI major bleeding events per 100 patient years compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about an increase;
(J) The method has a numerical value of approximately 0.44 for the number of TIMI major bleeding events per 100 patient years compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about an increase;
(K) The method does not result in a numerical increase in the number of lethal bleeding events per 100 patient years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
(L) The method provides a numerical increase of approximately 0.05 to the number of intracranial hemorrhage events per 100 patient years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Bring about;
(M) The method is less than 0.05% in Kaplan-Meier rate of lethal hemorrhage at 3 years compared to a regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient The difference between; or
(N) The method reduces the Kaplan-Meier rate of intracranial hemorrhage at 3 years to less than 0.1% compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Make a difference
The method according to any one of [1] to [9], wherein at least one of the following conditions is satisfied.
[11] The method according to any one of [1] to [10], wherein the method satisfies a condition including the condition described in (d) of [9] and the condition described in (a) of [10] the method of.
[12] The method according to any one of [1] to [10], wherein the method satisfies a condition including the condition described in (d) of [9] and the condition described in (b) of [10] the method of.
[13] The method according to any one of [1] to [10], wherein the method satisfies a condition including the condition described in (d) of [9] and the condition described in (c) of [10] the method of.
[14] The method according to any one of [1] to [10], wherein the method satisfies a condition including the condition described in (d) of [9] and the condition described in (d) of [10] the method of.
[15] The method according to any one of [1] to [10], wherein the method satisfies a condition including the condition described in (d) of [9] and the condition described in (e) of [10] the method of.
[16] The method according to any one of [1] to [15], wherein the pharmaceutical composition comprising 60 mg of ticagrelor and a pharmaceutically acceptable carrier is an orally administered tablet.
[17] A bulking agent wherein the tablet is present in an amount of 20-70 wt%, a binder present in an amount of 3-6 wt%, a disintegrant present in an amount of 2-6 wt%, and 0.5- The method of [16], comprising a lubricant present in an amount of 1% by weight.
[18] In a patient in need thereof comprising the step of administering to said patient twice a day said pharmaceutical composition comprising 60 mg of ticagrelor and a pharmaceutically acceptable carrier. A method of reducing the composite endpoint rate of vascular death, myocardial infarction, or stroke;
The patient has or may have had acute coronary syndrome;
A daily maintenance dose of 75 mg to 150 mg of aspirin is also administered to the patient;
A method wherein the composite endpoint rate in said patient is reduced compared to a dosing regimen wherein a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient.
[19] The method of [18], wherein the patient has acute coronary syndrome.
[20] The method according to [18], wherein the daily maintenance dose of aspirin is 75 mg to 100 mg.

Claims (20)

In a patient recognized need, comprising administering to a patient a pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier twice daily, cardiovascular death, myocardium A method of reducing the composite endpoint rate of infarction or stroke;
The patient has a history of myocardial infarction;
A daily maintenance dose of 75 mg to 150 mg of aspirin is also administered to the patient;
The method wherein the composite endpoint rate in the patient is reduced compared to a dosing regimen wherein a daily maintenance dose of the 75 mg to 150 mg aspirin alone is administered to the patient.   2. The method of claim 1, wherein the daily maintenance dose of the aspirin is 75 mg to 100 mg.   3. The patient has a history of myocardial infarction for at least 12 months prior to twice daily administration of the pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier. The method described in 1.   The patient has a history of myocardial infarction for 12 to 36 months prior to twice daily administration of the pharmaceutical composition comprising 60 mg ticagrelor and a pharmaceutically acceptable carrier. 4. The method according to any one of 3.   5. The method according to any one of claims 1-4, wherein the patient has a history of myocardial infarction as a result of acute coronary syndrome.   Prior to the administration, a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier was administered to the patient twice a day for a portion of 12 months after the acute coronary syndrome. The method of claim 5.   The pharmaceutical composition comprising 90 mg ticagrelor and a pharmaceutically acceptable carrier was administered to the patient twice a day for 12 months after the acute coronary syndrome prior to the administration. The method described.   Prior to twice daily administration of a pharmaceutical composition comprising 90 mg of ticagrelor and a pharmaceutically acceptable carrier in a portion of 12 months after said acute coronary syndrome, The method according to claim 6 or 7, wherein a pharmaceutical composition is administered to the patient. (A) The method reduces the absolute risk of the composite endpoint of cardiovascular mortality, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Reduce numerically;
(B) The method is less than 1 for the combined endpoint of cardiovascular death, myocardial infarction, or stroke as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Cause a relative risk of;
(C) Kaplan Meier of the composite endpoint of cardiovascular death, myocardial infarction, or stroke as compared to a dosing regimen wherein a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Reduce the rate numerically;
(D) The method provides statistics on the composite endpoint rate of cardiovascular mortality, myocardial infarction, or stroke as compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a significant reduction in chemistry;
(E) The method provides statistics on the composite endpoint of cardiovascular death, myocardial infarction, or stroke as compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Resulting in a relative risk significantly less than 1;
(F) the method results in a Kaplan-Meier rate of approximately 7.8% for the composite endpoint of cardiovascular death, myocardial infarction, or stroke at year 3;
(G) Time to first composite endpoint of cardiovascular death, myocardial infarction, or stroke, as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Results in a hazard ratio of less than 1;
(H) for patients with a composite endpoint event of cardiovascular death, myocardial infarction, or stroke, as compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Cause a numerical drop in percentage;
(I) time to first composite endpoint of cardiovascular mortality, myocardial infarction, or stroke as compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient; Results in a hazard ratio that is statistically significantly less than 1,
(J) the first combined end of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Bring a hazard ratio of about 0.84 to the time to point,
(K) the first combined end of cardiovascular death, myocardial infarction, or stroke at year 3 compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Bring a hazard ratio of 0.74-0.95 to the time to point,
(I) the first combination of cardiovascular death, myocardial infarction, or stroke event at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient The hazard ratio of 0.74 to 0.95 of time to endpoint yields a 95% confidence interval,
(M) the combined endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 as compared to a regimen wherein a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Reduce the absolute risk of about 1.27%;
(N) the combined endpoint of cardiovascular death, myocardial infarction, or stroke at year 3 as compared to a regimen wherein a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient Results in a relative risk reduction of approximately 17%;
(O) the combined endpoint of cardiovascular death, myocardial infarction, or stroke at 3 years compared to a regimen wherein a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient; Reduce the Kaplan-Meier rate by approximately 1.2%;
(P) Compound endpoint event of cardiovascular mortality, myocardial infarction, or stroke at year 3 compared to a dosing regimen where the daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Reduce the percentage of patients with approximately 1.3%;
(Q) the method results in a numerical reduction in cardiovascular mortality compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient; or (r) method Wherein the daily maintenance dose of 75 mg to 150 mg of aspirin alone meets at least one of the conditions leading to a numerical decrease in total mortality compared to a dosing regimen administered to the patient. The method as described in any one of -8. (A) The method does not result in a hazard ratio of more than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient;
(B) The method has a hazard ratio that is nominally significantly greater than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not bring;
(C) The method does not result in a hazard ratio of more than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient;
(D) The method results in a hazard ratio that is nominally significantly greater than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Absent;
(E) the method does not pose a relative risk of more than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
(F) The method has a relative risk of nominally significantly greater than 1 for 3 years of lethal bleeding compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Does not bring;
(G) the method does not pose a relative risk of more than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
(H) The method results in a relative risk that is nominally significantly greater than 1 for intracranial hemorrhage at year 3 compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Absent;
(I) The method shows a numerical value of less than 0.5 for the number of TIMI major bleeding events per 100 patient years compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about an increase;
(J) The method has a numerical value of approximately 0.44 for the number of TIMI major bleeding events per 100 patient years compared to a dosing schedule in which a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient. Bring about an increase;
(K) The method does not result in a numerical increase in the number of lethal bleeding events per 100 patient years compared to a regimen in which a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient;
(L) The method provides a numerical increase of approximately 0.05 to the number of intracranial hemorrhage events per 100 patient years compared to a regimen in which a daily maintenance dose of only 75 mg to 150 mg of aspirin is administered to the patient. Bring about;
(M) The method is less than 0.05% in Kaplan-Meier rate of lethal hemorrhage at 3 years compared to a regimen where a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient Or (n) the Kaplan-Meier rate of intracranial hemorrhage at year 3 compared to a dosing regimen where a daily maintenance dose of 75 mg to 150 mg of aspirin alone is administered to the patient, 10. A method according to any one of the preceding claims, satisfying at least one of the conditions leading to a difference of less than 0.1%.   The condition according to any one of claims 1 to 10, wherein the condition is satisfied by a method comprising the condition according to claim 9 (d) and the condition according to claim 10 (a). Method.   The condition according to any one of claims 1 to 10, wherein the condition is satisfied by a method comprising the condition according to claim 9 (d) and the condition according to claim 10 (b). Method.   The condition according to any one of claims 1 to 10, wherein the condition is satisfied by a method comprising the condition according to claim 9 (d) and the condition according to claim 10 (c). Method.   The condition according to any one of claims 1 to 10, wherein the condition is satisfied by a method comprising the condition according to claim 9 (d) and the condition according to claim 10 (d). Method.   The condition according to any one of claims 1 to 10, wherein the condition is satisfied by a method comprising the condition according to claim 9 (d) and the condition according to claim 10 (e). Method.   The method according to any one of claims 1 to 15, wherein the pharmaceutical composition comprising 60 mg of ticagrelor and a pharmaceutically acceptable carrier is a tablet for oral administration.   A bulking agent wherein the tablet is present in an amount of 20-70 wt%, a binder present in an amount of 3-6 wt%, a disintegrant present in an amount of 2-6 wt%, and 0.5-1 wt% The method of claim 16 comprising a lubricant present in an amount of. Cardiovascular mortality in a recognized patient comprising the step of administering to said patient twice a day said pharmaceutical composition comprising 60 mg of ticagrelor and a pharmaceutically acceptable carrier A method of reducing the composite endpoint rate of myocardial infarction or stroke;
The patient has or may have had acute coronary syndrome;
A daily maintenance dose of 75 mg to 150 mg of aspirin is also administered to the patient;
A method wherein the composite endpoint rate in said patient is reduced compared to a dosing regimen wherein a daily maintenance dose of 75 mg to 150 mg aspirin alone is administered to the patient.   The method of claim 18, wherein the patient has acute coronary syndrome.   The method of claim 18, wherein the daily maintenance dose of aspirin is 75 mg to 100 mg.